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Toker D, Chiang JN, Vespa PM, Schnakers C, Monti MM. The Dipeptidyl Peptidase-4 Inhibitor Saxagliptin as a Candidate Treatment for Disorders of Consciousness: A Deep Learning and Retrospective Clinical Analysis. Neurocrit Care 2025:10.1007/s12028-025-02217-0. [PMID: 39904872 DOI: 10.1007/s12028-025-02217-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes. METHODS To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury. RESULTS Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage. CONCLUSIONS Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.
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Affiliation(s)
- Daniel Toker
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Jeffrey N Chiang
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Paul M Vespa
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Caroline Schnakers
- Research Institute, Casa Colina Hospital and Centers for Healthcare, Pomona, CA, USA
| | - Martin M Monti
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
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Huang KH, Yang Y, Gau SY, Tsai TH, Lee CY. Association between dipeptidyl peptidase-4 inhibitor use and risk of Parkinson's disease among patients with diabetes mellitus: a retrospective cohort study. Aging (Albany NY) 2024; 16:11994-12007. [PMID: 39177655 PMCID: PMC11386917 DOI: 10.18632/aging.206074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 07/11/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM). METHODS Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust P-values and reduce the false positive rate. RESULTS Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted P = .886) and 1.06 (95% CI: 0.75-1.50; adjusted P = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted P > .05). CONCLUSIONS DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Yih Yang
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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Lee JM, Yoon JH, Maeng HJ, Kim YC. Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human Extrapolation. Pharmaceutics 2024; 16:280. [PMID: 38399334 PMCID: PMC10892660 DOI: 10.3390/pharmaceutics16020280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/09/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated drug-drug interactions (DDIs) between saxagliptin and nicardipine using a physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in vitro parameters were gathered from experiments or the literature to construct PBPK models for each drug in rats. These models were integrated to predict the DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing parameters using experimental rat plasma concentrations after co-administration of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin plasma concentration significantly increased, resulting in a 2.60-fold rise in AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of the rat PBPK model was applied to humans, creating a model capable of predicting DDIs between the two drugs in humans. Simulation from the human PBPK model indicated that nicardipine co-administration in humans resulted in a nearly unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no clinically significant changes and revealing a lack of direct translation of animal interaction results to humans. The animal-to-human PBPK model extrapolation used in this study could enhance the reliability of predicting drug interactions in clinical settings where DDI studies are challenging.
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Affiliation(s)
- Jeong-Min Lee
- Department of Digital Anti-Aging Healthcare, Inje University, Gimhae 50834, Republic of Korea;
| | - Jin-Ha Yoon
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea;
| | - Han-Joo Maeng
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea;
| | - Yu Chul Kim
- Department of Digital Anti-Aging Healthcare, Inje University, Gimhae 50834, Republic of Korea;
- Department of Pharmaceutical Engineering, Inje University, Gimhae 50834, Republic of Korea
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Kim KY, Jeong YJ, Park SY, Park EJ, Jeon JH, Song IS, Liu KH. Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats. Pharmaceutics 2024; 16:106. [PMID: 38258116 PMCID: PMC10819019 DOI: 10.3390/pharmaceutics16010106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.
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Affiliation(s)
- Ki-Young Kim
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Yeo-Jin Jeong
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - So-Young Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Eun-Ji Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Ji-Hyeon Jeon
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Im-Sook Song
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
| | - Kwang-Hyeon Liu
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea; (K.-Y.K.); (Y.-J.J.); (S.-Y.P.); (E.-J.P.); (J.-H.J.)
- Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea
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Ramos H, Bogdanov P, Simó R, Deàs-Just A, Hernández C. Transcriptomic Analysis Reveals That Retinal Neuromodulation Is a Relevant Mechanism in the Neuroprotective Effect of Sitagliptin in an Experimental Model of Diabetic Retinopathy. Int J Mol Sci 2022; 24:ijms24010571. [PMID: 36614016 PMCID: PMC9820711 DOI: 10.3390/ijms24010571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Transcriptome analysis was performed, comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily and the retinas of 10 additional db/db mice that received vehicle eye drops. Ten non-diabetic mice (db/+) were used as a control group. The Gene Ontology (GO) and Reactome databases were used to perform the gene set enrichment analysis (GSEA) in order to explore the most enriched biological pathways among the groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission is the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesicle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of the macromolecule biosynthetic process with positive regulation of cell communication, which provides beneficial effects for the neuronal metabolism. This study suggests that topical administration of sitagliptin ameliorates the abnormalities on presynaptic and postsynaptic signal transmission during experimental DR and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.
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Affiliation(s)
- Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Correspondence: (P.B.); (C.H.)
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Anna Deàs-Just
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Correspondence: (P.B.); (C.H.)
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Xie Y, Zhou Q, He Q, Wang X, Wang J. Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition. Acta Pharm Sin B 2022. [DOI: 10.1016/j.apsb.2022.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Butrovich MA, Tang W, Boulton DW, Nolin TD, Sharma P. Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Impact of Chronic Kidney Disease on CYP3A4-Mediated Metabolism of Saxagliptin. J Clin Pharmacol 2022; 62:1018-1029. [PMID: 35247279 PMCID: PMC9545133 DOI: 10.1002/jcph.2043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/25/2022] [Indexed: 11/25/2022]
Abstract
We characterized the impact of chronic kidney disease (CKD) on the cytochrome P450 (CYP) 3A4–mediated metabolism of saxagliptin to its metabolite, 5‐hydroxysaxagliptin, using a physiologically based pharmacokinetic (PBPK) model. A PBPK model of saxagliptin and its CYP3A4 metabolite, 5‐hydroxysaxagliptin, was constructed and validated for oral doses ranging from 5 to 100 mg. The observed ratios of area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) between healthy subjects and subjects with CKD were compared with those predicted using PBPK model simulations. Simulations were performed with virtual CKD populations having decreased CYP3A4 activity (ie, 64%‐75% of the healthy subjects’ CYP3A4 abundance) and preserved CYP3A4 activity (ie, 100% of the healthy subjects’ CYP3A4 abundance). We found that simulations using decreased CYP3A4 activity generally overpredicted the ratios of saxagliptin AUC and Cmax in CKD compared with those using preserved CYP3A4 activity. Similarly, simulations using decreased CYP3A4 activity underpredicted the ratio of 5‐hydroxysaxagliptin AUC in moderate and severe CKD compared with simulations using preserved CYP3A4 activity. These findings suggest that decreased CYP3A4 activity in CKD underpredicts saxagliptin clearance compared with that observed clinically. Preserving CYP3A4 activity in CKD more closely estimates saxagliptin clearance and 5‐hydroxysaxagliptin exposure changes observed in vivo. Our findings suggest that there is no clinically meaningful impact of CKD on the metabolism of saxagliptin by CYP3A4. Since saxagliptin is not a highly sensitive substrate and validated probe for CYP3A4, this work represents a case study of a CYP3A4 substrate‐metabolite pair and is not a generalization for all CYP3A4 substrates.
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Affiliation(s)
- Morgan A. Butrovich
- Department of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghPennsylvaniaUSA
| | - Weifeng Tang
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
| | - David W. Boulton
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaGaithersburgMarylandUSA
| | - Thomas D. Nolin
- Department of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghPennsylvaniaUSA
| | - Pradeep Sharma
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUK
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Tsai WH, Sung FC, Chiu LT, Shih YH, Tsai MC, Wu SI. Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study. Front Pharmacol 2022; 13:765446. [PMID: 35281896 PMCID: PMC8904427 DOI: 10.3389/fphar.2022.765446] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Previous findings on using Glucagon-like peptide-1 receptor agonist (GLP1-RA) as an antidepressant were conflicting, lacking large-scale studies. We used population-based data to investigate depression and anxiety risk in diabetic patients receiving the medication. Methods: From claims records of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified cohorts of 10,690 GLP1-RA users and 42,766 propensity score-matched patients without GLP1-RA use from patients with diabetes mellitus (DM) diagnosed in 2011–2017, matched by age, gender, index year, occupation, urbanization, comorbidities, and medications. Incidence, hazard ratios (HR) and 95% confidence interval (CI) of depression and/or anxiety were estimated by the end of 2017. Results: The overall combined incidence of anxiety and/or depression was lower in GLP1-RA users than in non-users (6.80 versus 9.36 per 1,000 person-years), with an adjusted HR adjusted hazard ratio (aHR) of 0.8 (95% CI: 0.67–0.95) after controlling for covariates. The absolute incidence reduction was greater in anxiety (2.13 per 1,000 person-years) than in depression (0.41 per 1,000 person-years). The treatment effectiveness was significant for women. Patients taking GLP1-RA for longer than 180 days had the incidence of anxiety reduced to 2.93 per 1,000 person-years, with an aHR of 0.41 (95%CI: 0.27–0.61), compared to non-users. Dulaglutide could significantly decrease risks of both anxiety and depression. Conclusion: Patients with DM receiving GLP1-RA therapy have a greater reduction of the risk of anxiety than that of depression. Our findings strengthen previous research that advocated possible anti-depressant or anxiolytic effects of GLP1-RA and may lead to improved treatment adherence among patients with DM.
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Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Fung-Chang Sung
- Management Office for Health Data (DryLab), Clinical Trial Research Center (CTC), China Medical University Hospital, Taichung, Taiwan
- Department of Health Services Administration, College of Public Health, China Medical University, Taichung, Taiwan
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Lu-Ting Chiu
- Management Office for Health Data (DryLab), Clinical Trial Research Center (CTC), China Medical University Hospital, Taichung, Taiwan
| | - Ying-Hsiu Shih
- Management Office for Health Data (DryLab), Clinical Trial Research Center (CTC), China Medical University Hospital, Taichung, Taiwan
| | - Ming-Chieh Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Shu-I Wu
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan
- *Correspondence: Shu-I Wu,
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Bogdanov P, Ramos H, Valeri M, Deàs-Just A, Huerta J, Simó R, Hernández C. Minimum Effective Dose of DPP-4 Inhibitors for Treating Early Stages of Diabetic Retinopathy in an Experimental Model. Biomedicines 2022; 10:biomedicines10020465. [PMID: 35203674 PMCID: PMC8962353 DOI: 10.3390/biomedicines10020465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/11/2022] [Accepted: 02/13/2022] [Indexed: 02/04/2023] Open
Abstract
The neurovascular unit (NVU) plays an essential role in the development of diabetic retinopathy (DR). We previously reported that the topical administration (eye drops) of sitagliptin and saxagliptin, two dipeptidyl peptidase-4 inhibitors (DPP-4i), prevents retinal neurodegeneration and vascular leakage in db/db mice. The aim of the present study is to evaluate the minimum effective dose of the topical administration of these DPP-4i. For this purpose, sitagliptin and saxagliptin were tested at different concentrations (sitagliptin: 1 mg/mL, 5 and 10 mg/mL, twice per day; saxagliptin: 1 and 10 mg/mL, once or twice per day) in db/db mice. As end points of efficacy, the hallmarks of NVU impairment were evaluated: reactive gliosis, neural apoptosis, and vascular leakage. These parameters were assessed by immunohistochemistry, cell counting, and the Evans blue method, respectively. Our results demonstrated that the minimum effective dose is 5 mg/mL twice per day for sitagliptin, and 10 mg/mL twice per day for saxagliptin. In conclusion, this study provides useful results for the design of future preclinical regulatory studies and for planning clinical trials.
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Affiliation(s)
- Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Marta Valeri
- Unit of High Technology, Vall d’Hebron Research Institute, 08035 Barcelona, Spain;
| | - Anna Deàs-Just
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
| | - Jordi Huerta
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Correspondence: (R.S.); (C.H.); Tel.: +34-934-894-172 (C.H.)
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, 08035 Barcelona, Spain; (P.B.); (H.R.); (A.D.-J.); (J.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Correspondence: (R.S.); (C.H.); Tel.: +34-934-894-172 (C.H.)
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Setayesh-Mehr Z, Poorsargol M. HL-7 and HL-10 Peptides Stimulate Insulin Secretion in the INS-1 Insulinoma Cell Line through Incretin-Dependent Pathway and Increasing the Glucose Uptake in L6 Myoblast. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10249-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Li G, Yi B, Liu J, Jiang X, Pan F, Yang W, Liu H, Liu Y, Wang G. Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy. Front Pharmacol 2021; 12:746594. [PMID: 34737703 PMCID: PMC8560969 DOI: 10.3389/fphar.2021.746594] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/13/2021] [Indexed: 11/26/2022] Open
Abstract
We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.
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Affiliation(s)
- Gang Li
- Beijing Adamadle Biotech Co, Ltd., Beijing, China
| | - Bowen Yi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingtong Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoquan Jiang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Fulu Pan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wenning Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Haibo Liu
- Chinese Academy of Medical Sciences and Peking Union Medical College, Institute of Medicinal Plant Development, Beijing, China
| | - Yang Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Guopeng Wang
- Zhongcai Health (Beijing) Biological Technology Development Co, Ltd., Beijing, China
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12
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Qian XK, Zhang J, Li XD, Song PF, Zou LW. Research Progress on Dipeptidyl Peptidase Family: Structure, Function and Xenobiotic Metabolism. Curr Med Chem 2021; 29:2167-2188. [PMID: 34525910 DOI: 10.2174/0929867328666210915103431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 11/22/2022]
Abstract
Prolyl-specific peptidases or proteases, including Dipeptidyl Peptidase 2, 4, 6, 8, 9, 10, Fibroblast Activation Protein, prolyl endopeptidase and prolyl carboxypeptidase, belong to the dipeptidyl peptidase family. In human physiology and anatomy, they have homology amino acid sequences, similarities in structure, but play distinct functions and roles. Some of them also play important roles in the metabolism of drugs containing endogenous peptides, xenobiotics containing peptides, and exogenous peptides. The major functions of these peptidases in both the metabolism of human health and bioactive peptides are of significant importance in the development of effective inhibitors to control the metabolism of endogenous bioactive peptides. The structural characteristics, distribution of tissue, endogenous substrates, and biological functions were summarized in this review. Furthermore, the xenobiotics metabolism of the dipeptidyl peptidase family is illustrated. All the evidence and information summarized in this review would be very useful for researchers to extend the understanding of the proteins of these families and offer advice and assistance in physiology and pathology studies.
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Affiliation(s)
- Xing-Kai Qian
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai. China
| | - Jing Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai. China
| | - Xiao-Dong Li
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai. China
| | - Pei-Fang Song
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai. China
| | - Li-Wei Zou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai. China
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13
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Mohamad AM, Andac CA, Andac SC. Cross Referencing 2D-LC Determination of Intact Gliptins in Urine. J Chromatogr Sci 2021; 58:907-914. [PMID: 32875329 DOI: 10.1093/chromsci/bmaa059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/11/2020] [Accepted: 08/08/2020] [Indexed: 11/15/2022]
Abstract
Dipeptidyl peptidase-4 inhibitors, so-called gliptins, constitute a fairly novel class of oral hypoglycemic agents. The development and validation of an automated online SPE-LC-UV method to determine intact sitagliptin, saxagliptin, vildagliptin and metformin simultaneously in human urine samples were performed. For the two-dimensional chromatographic separation, a Gemini C18 (250.0 × 4.6 mm i.d., 110 A0, 5.0 μ) analytical column and a gradient elution with 10.0 mM o-phosphoric acid and methanol and for the online SPE analysis of urine samples, a LiChrospher® ADS SPE-column (20.0 mm × 2.0 mm i.d., 25.0 μm) were used through the study. The fractionation, transfer, elution and separation of the spiked urine samples were achieved in just 9.57 min runtime with 12.0 mL of solvent consumption which was green and economical compared to other sample preparation methods. The calibration curves were determined to be linear in a wide range of 0.10-100.00 μg/mL with satisfactory regression coefficients. Method developed for two-dimensional determination of gliptins would be useful as a reference in therapeutic drug monitoring and screening for forensic medical cases which involve the abuse, unintentional or misuse of multiple gliptins in terms of its practical use, easy detection and reliable results.
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Affiliation(s)
- Amal M Mohamad
- Department of Analytical Chemistry, Faculty of Pharmacy, Istanbul University, 7-1, Suleymaniye, 34116, Istanbul, Turkey
| | - Cenk A Andac
- Department of Medicinal Chemistry, School of Pharmacy, Istinye University, Topkapi Campus, Teyyareci Sami Street, No.3, 34010 Zeytinburnu, Istanbul, Turkey
| | - Sena Caglar Andac
- Department of Analytical Chemistry, Faculty of Pharmacy, Istanbul University, 7-1, Suleymaniye, 34116, Istanbul, Turkey
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14
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Orime K, Terauchi Y. Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother 2020; 21:2101-2114. [DOI: 10.1080/14656566.2020.1803280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Kazuki Orime
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
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15
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Gu N, Park SI, Chung H, Jin X, Lee S, Kim TE. Possibility of pharmacokinetic drug interaction between a DPP-4 inhibitor and a SGLT2 inhibitor. Transl Clin Pharmacol 2020; 28:17-33. [PMID: 32274378 PMCID: PMC7136081 DOI: 10.12793/tcp.2020.28.e4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/23/2022] Open
Abstract
Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.
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Affiliation(s)
- Namyi Gu
- Department of Clinical Pharmacology and Therapeutics, Clinical Trial Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Korea
| | - Sang-In Park
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Korea
| | - Hyewon Chung
- Department of Clinical Pharmacology and Toxicology, Korea University Guro Hospital, Seoul, Korea
| | - Xuanyou Jin
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - Tae-Eun Kim
- Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Korea
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16
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Makrilakis K. The Role of DPP-4 Inhibitors in the Treatment Algorithm of Type 2 Diabetes Mellitus: When to Select, What to Expect. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16152720. [PMID: 31366085 PMCID: PMC6696077 DOI: 10.3390/ijerph16152720] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially associated with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiology, its treatment is varied and based upon a multitude of pharmacologic agents aiming to tackle the many aspects of the disease pathophysiology (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or “gliptins”) represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biological activity of the “incretin” hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiological problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.
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Affiliation(s)
- Konstantinos Makrilakis
- National and Kapodistrian University of Athens Medical School, Laiko General Hospital, 17 Ag. Thoma St., 11527 Athens, Greece.
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17
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Lundkvist P, Pereira MJ, Kamble PG, Katsogiannos P, Langkilde AM, Esterline R, Johnsson E, Eriksson JW. Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes. J Clin Endocrinol Metab 2019; 104:193-201. [PMID: 30137410 DOI: 10.1210/jc.2018-00969] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/09/2018] [Indexed: 01/14/2023]
Abstract
CONTEXT The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown. OBJECTIVE To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed. DESIGN, SETTING, AND PATIENTS A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin. INTERVENTIONS Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed. RESULTS Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D. CONCLUSION The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.
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Affiliation(s)
- Per Lundkvist
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Maria J Pereira
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Prasad G Kamble
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | | | | | - Eva Johnsson
- AstraZeneca Research and Development, Mölndal, Sweden
| | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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18
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Ren S, Boulton DW. Pharmacokinetic Interaction Study Between Saxagliptin and Omeprazole, Famotidine, or Magnesium and Aluminum Hydroxides Plus Simethicone in Healthy Subjects: An Open-Label Randomized Crossover Study. Clin Pharmacol Drug Dev 2018; 8:549-558. [PMID: 30500110 DOI: 10.1002/cpdd.634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 10/26/2018] [Indexed: 11/09/2022]
Abstract
Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.
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Affiliation(s)
- Song Ren
- Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD, USA
| | - David W Boulton
- Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gaithersburg, MD, USA
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19
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Wallgren J, Vikingsson S, Åstrand A, Josefsson M, Gréen H, Dahlén J, Wu X, Konradsson P. Synthesis and identifications of potential metabolites as biomarkers of the synthetic cannabinoid AKB-48. Tetrahedron 2018. [DOI: 10.1016/j.tet.2018.04.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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20
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Peng Y, Chang Q, Yang N, Gu S, Zhou Y, Yin L, Aa J, Wang G, Sun J. Quantitative determination of metformin, saxagliptin and 5-hydroxy saxagliptin simultaneously by hydrophilic interaction liquid chromatography - electrospray ionization mass spectrometry and its application to a bioequivalence study with a single-pill combination in human. J Chromatogr B Analyt Technol Biomed Life Sci 2018. [DOI: 10.1016/j.jchromb.2018.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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21
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Wallgren J, Vikingsson S, Johansson A, Josefsson M, Green H, Dahlén J, Wu X, Konradsson P. Synthesis and identification of an important metabolite of AKB-48 with a secondary hydroxyl group on the adamantyl ring. Tetrahedron Lett 2017. [DOI: 10.1016/j.tetlet.2017.02.077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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22
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Tramutola A, Arena A, Cini C, Butterfield DA, Barone E. Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer’s disease pathology. Expert Rev Neurother 2016; 17:59-75. [PMID: 27715341 DOI: 10.1080/14737175.2017.1246183] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Antonella Tramutola
- Department of Biochemical Sciences ‘A. Rossi-Fanelli’, Sapienza University of Rome, Roma, Italy
| | - Andrea Arena
- Department of Biochemical Sciences ‘A. Rossi-Fanelli’, Sapienza University of Rome, Roma, Italy
| | - Chiara Cini
- Department of Biochemical Sciences ‘A. Rossi-Fanelli’, Sapienza University of Rome, Roma, Italy
| | - D. Allan Butterfield
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
| | - Eugenio Barone
- Department of Biochemical Sciences ‘A. Rossi-Fanelli’, Sapienza University of Rome, Roma, Italy
- Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Santiago, Chile
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23
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Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, del Cañizo-Gómez FJ. Update on the treatment of type 2 diabetes mellitus. World J Diabetes 2016; 7:354-95. [PMID: 27660695 PMCID: PMC5027002 DOI: 10.4239/wjd.v7.i17.354] [Citation(s) in RCA: 366] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/02/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.
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24
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Shah PA, Shah JV, Sanyal M, Shrivastav PS. LC-MS/MS analysis of metformin, saxagliptin and 5-hydroxy saxagliptin in human plasma and its pharmacokinetic study with a fixed-dose formulation in healthy Indian subjects. Biomed Chromatogr 2016; 31. [PMID: 27508356 DOI: 10.1002/bmc.3809] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 07/28/2016] [Accepted: 08/08/2016] [Indexed: 01/29/2023]
Abstract
A specific and rapid liquid chromatography-tandem mass spectrometry method is proposed for the simultaneous determination of metformin (MET), saxagliptin (SAXA) and its active metabolite, 5-hydroxy saxagliptin (5-OH SAXA) in human plasma. Sample preparation was accomplished from 50 μL plasma sample by solid-phase extraction using sodium dodecyl sulfate as an ion-pair reagent. Reversed-phase chromatographic resolution of analytes was possible within 3.5 min on ACE 5CN (150 × 4.6 mm, 5 μm) column using acetonitrile and10.0 mm ammonium formate buffer, pH 5.0 (80:20, v/v) as the mobile phase. Triple quadrupole mass spectrometric detection was performed using electrospray ionization in the positive ionization mode. The calibration curves showed good linearity (r2 ≥ 0.9992) over the established concentration range with limit of quantification of 1.50, 0.10 and 0.20 ng/mL for MET, SAXA and 5-OH SAXA respectively. The extraction recoveries obtained from spiked plasma samples were highly consistent for MET (75.12-77.84%), SAXA (85.90-87.84%) and 5-OH SAXA (80.32-82.69%) across quality controls. The validated method was successfully applied to a bioequivalence study with a fixed-dose formulation consisting of 5 mg SAXA and 500 mg MET in 18 healthy subjects. The reproducibility of the assay was demonstrated by reanalysis of 87 incurred samples.
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Affiliation(s)
- Priyanka A Shah
- Department of Chemistry School of Sciences, Gujarat University, Ahmedabad, India
| | - Jaivik V Shah
- Department of Chemistry School of Sciences, Gujarat University, Ahmedabad, India
| | - Mallika Sanyal
- Department of Chemistry, St Xavier's College, Ahmedabad, India
| | - Pranav S Shrivastav
- Department of Chemistry School of Sciences, Gujarat University, Ahmedabad, India
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25
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Liu D, Ma X, Liu Y, Zhou H, Shi C, Wu F, Jiang J, Hu P. Quantitative prediction of human pharmacokinetics and pharmacodynamics of imigliptin, a novel DPP-4 inhibitor, using allometric scaling, IVIVE and PK/PD modeling methods. Eur J Pharm Sci 2016; 89:73-82. [PMID: 27108678 DOI: 10.1016/j.ejps.2016.04.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 04/18/2016] [Accepted: 04/19/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE To predict the pharmacokinetic/pharmacodynamic (PK/PD) profiles of imigliptin, a novel DPP-4 inhibitor, in first-in-human (FIH) study based on the data from preclinical species. METHODS Imigliptin was intravenously and orally administered to rats, dogs, and monkeys to assess their PK/PD properties. DPP-4 activity was the PD biomarker. PK/PD profiles of sitagliptin and alogliptin in rats and humans were obtained and digitized from literatures. PK/PD profiles of all dose levels for each drug in each species were analyzed using modeling approach. Human CL, Vss and PK profiles of imigliptin were then predicted using Allometric Scaling (AS), in vitro in vivo extrapolation (IVIVE), and the steady-state plasma drug concentration - mean residence time (Css-MRT) methods. In vitro EC50 corrected by fu and in vivo EC50 in rats corrected by interspecies difference of sitagliptin and alogliptin were utilized separately to predict imigliptin human EC50. The prediction by integrating all above methods was evaluated by comparing observed and simulated PK/PD profiles in healthy subjects. RESULTS Full PK/PD profiles in animal were summarized for imigliptin, sitagliptin and alogliptin. Imigliptin CL, Vss, and Fa were predicted to be 19.1L/h, 247L, and 0.81 in humans, respectively. Predicted imigliptin AUCs, AUECs, and Emax in humans were within 0.8-1.2 times of observed values whereas other predicted PK/PD parameters were within 0.5-1.5 times of observed values. CONCLUSIONS By integrating available preclinical and clinical data, FIH PK/PD profiles of imigliptin could be accurately predicted.
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Affiliation(s)
- Dongyang Liu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Xifeng Ma
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Yang Liu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Huimin Zhou
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Chongtie Shi
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Frank Wu
- XuanZhu Pharma Co., Ltd., Jinan, Shandong, China
| | - Ji Jiang
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China
| | - Pei Hu
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
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26
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Anderson R, Hayes J, Stephens JW. Pharmacokinetic, pharmacodynamic and clinical evaluation of saxagliptin in type 2 diabetes. Expert Opin Drug Metab Toxicol 2016; 12:467-73. [PMID: 26878666 DOI: 10.1517/17425255.2016.1154044] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Dipeptide peptidase-4 (DPP-4) inhibitors such as saxagliptin are established and efficacious oral therapies in the management of type 2 diabetes. These agents have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes. AREAS COVERED This review examines the pharmacokinetics, efficacy and tolerability of saxagliptin for the management of type 2 diabetes. EXPERT OPINION Saxagliptin is routinely used in the management of type 2 diabetes as monotherapy, and in combination with other oral agents and insulin. Robust clinical trials have shown consistent improvements in glycated hemoglobin, fasting and postprandial glucose levels, with few adverse effects. The agent is well tolerated with low rates of hypoglycemia in the absence of insulin or sulphonylurea therapy.
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Affiliation(s)
- Rose Anderson
- a Department of Diabetes & Endocrinology , Morriston Hospital, ABM University Health Board , Swansea , UK
| | - Jennifer Hayes
- a Department of Diabetes & Endocrinology , Morriston Hospital, ABM University Health Board , Swansea , UK
| | - Jeffrey W Stephens
- a Department of Diabetes & Endocrinology , Morriston Hospital, ABM University Health Board , Swansea , UK.,b Diabetes Research Group , Institute of Life Sciences, Swansea University , Swansea , UK
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27
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Abstract
Cardiovascular disease risk and all-cause mortality are largely predicted by physical fitness. Exercise stimulates vascular mitochondrial biogenesis through endothelial nitric oxide synthase (eNOS), sirtuins, and PPARγ coactivator 1α (PGC-1α), a response absent in diabetes and hypertension. We hypothesized that an agent regulating eNOS in the context of diabetes could reconstitute exercise-mediated signaling to mitochondrial biogenesis. Glucagon-like peptide 1 (GLP-1) stimulates eNOS and blood flow; we used saxagliptin, an inhibitor of GLP-1 degradation, to test whether vascular mitochondrial adaptation to exercise in diabetes could be restored. Goto-Kakizaki (GK) rats, a nonobese, type 2 diabetes model, and Wistar controls were exposed to an 8-day exercise intervention with or without saxagliptin (10 mg·kg−1·d−1). We evaluated the impact of exercise and saxagliptin on mitochondrial proteins and signaling pathways in aorta. Mitochondrial protein expression increased with exercise in the Wistar aorta and decreased or remained unchanged in the GK animals. GK rats treated with saxagliptin plus exercise showed increased expression of mitochondrial complexes, cytochrome c, eNOS, nNOS, PGC-1α, and UCP3 proteins. Notably, a 3-week saxagliptin plus exercise intervention significantly increased running time in the GK rats. These data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a diabetic rodent model and may augment the impact of exercise on the vasculature.
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Xia Z, Wei H, Duan J, Zhou T, Yang Z, Xu F. Chronic unpredicted mild stress-induced depression alter saxagliptin pharmacokinetics and CYP450 activity in GK rats. PeerJ 2016; 4:e1611. [PMID: 26819853 PMCID: PMC4727972 DOI: 10.7717/peerj.1611] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 12/29/2015] [Indexed: 12/19/2022] Open
Abstract
Background. This study was to explore the pharmacokinetics of saxagliptin (Sax) in Goto–Kakizaki (GK) rats complicated with depression induced by chronic unpredicted mild stress (CUMS). The comorbidity of diabetic patients with depression is becoming more and more epidemic. Whether depression mental disorder alters the pharmacokinetics of hypoglycemic drugs in diabetes patients is not clear. Methods. Five-week-old male GK rats were kept in the cage for 7 weeks in a specific pathogen free (SPF)-grade lab until the emergence of diabetes and were then divided into two groups: control group and depression model group. Rats in the CUMS-induced depression group were exposed to a series of stressors for 8 weeks. Plasma serotonin and dopamine levels and behavior of open-field test were used to confirm the establishment of the depression model. All rats were given 0.5 mg/kg Sax orally after 8 weeks and blood samples were collected at different time points. The Sax concentration was assayed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The CYP450 activity of the liver microsomes was determined by using cocktails of probe drugs in which the activities of CYP enzymes were assessed through the determination of the production of the probe drugs. Results. Statistically significant differences in Sax pharmacokinetics were observed for area under curve, clearance, peak concentration, peak time and mean residence time between the depression rats and the control rats, while no statistical differences were observed for half-time and distribution volume by HPLC-MS/MS analysis. The CYP450 activity had different changes in the depression group. Conclusions. These results indicated that CUMS-induced depression alters the drug metabolic process of Sax and CYP450 activity of the liver microsomal enzymes in GK rats.
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Affiliation(s)
- Zhengchao Xia
- Department of Pharmacy, Fengxian Central Hospital Graduate Training Base, Liaoning Medical University , Shanghai , China
| | - Hongyan Wei
- Department of Pharmacy, Southern Medical University Affiliated Fengxian Central Hospital , Shanghai , China
| | - Jingjing Duan
- Department of Pharmacy, Southern Medical University Affiliated Fengxian Central Hospital , Shanghai , China
| | - Ting Zhou
- Department of Pharmacy, Southern Medical University Affiliated Fengxian Central Hospital , Shanghai , China
| | - Zhen Yang
- Department of Pharmacy, Fengxian Central Hospital Graduate Training Base, Liaoning Medical University , Shanghai , China
| | - Feng Xu
- Department of Pharmacy, Fengxian Central Hospital Graduate Training Base, Liaoning Medical University, Shanghai, China; Department of Pharmacy, Southern Medical University Affiliated Fengxian Central Hospital, Shanghai, China
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Nakamaru Y, Akahoshi F, Iijima H, Hisanaga N, Kume T. Tissue distribution of teneligliptin in rats and comparisons with data reported for other dipeptidyl peptidase-4 inhibitors. Biopharm Drug Dispos 2016; 37:142-155. [PMID: 26749565 PMCID: PMC5074247 DOI: 10.1002/bdd.2003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/26/2015] [Accepted: 12/29/2015] [Indexed: 01/26/2023]
Abstract
We investigated the tissue distribution of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, in rats, and compared it with tissue distributions previously reported for other DPP-4 inhibitors. Following the oral administration of [14 C]teneligliptin to Sprague-Dawley rats, it was predominantly distributed to the kidney and liver, followed by the lung, spleen, and pituitary gland. The elimination half-life (t1/2 ) of [14 C]teneligliptin was 68.3 and 69.0 h in the kidney and liver, respectively; these values were about 10 times greater than the plasma t1/2 . Of note, the elimination of [14 C]teneligliptin from tissues with high DPP-4 activity (kidney, liver, and lung) was slower in wild-type rats than in DPP-4-deficient rats, especially in the kidney. By contrast, in the heart and pancreas, which weakly express DPP-4, we observed no difference in [14 C]teneligliptin concentrations between the two animal strains. In the kidney, most radioactivity was attributable to unchanged teneligliptin from 0.5 to 72 h after administration. The marked difference in the distribution of [14 C]teneligliptin between the two strains suggests that the high binding affinity of teneligliptin for DPP-4 is involved in its tissue distribution. The currently marketed DPP-4 inhibitors are highly distributed to the liver, kidney, and lung, but the extent of tissue distribution varies greatly among the drugs. The differences in the tissue distributions of DPP-4 inhibitors might be related to differences in their pleiotropic effects. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yoshinobu Nakamaru
- Clinical Pharmacology Department, Development Division, Mitsubishi Tanabe Pharma Co, Chuo-ku, Tokyo, Japan
| | - Fumihiko Akahoshi
- Research Unit C, Research Division, Mitsubishi Tanabe Pharma Co, Toda, Saitama, Japan
| | - Hiroaki Iijima
- Medical Affairs Department, Mitsubishi Tanabe Pharma Co, Chuo-ku, Tokyo, Japan
| | - Noriko Hisanaga
- DMPK Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Co, Kisarazu, Chiba, Japan
| | - Toshiyuki Kume
- DMPK Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Co, Kisarazu, Chiba, Japan
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Lim SW, Jin JZ, Jin L, Jin J, Li C. Role of dipeptidyl peptidase-4 inhibitors in new-onset diabetes after transplantation. Korean J Intern Med 2015; 30:759-70. [PMID: 26552451 PMCID: PMC4642005 DOI: 10.3904/kjim.2015.30.6.759] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 10/14/2015] [Indexed: 02/06/2023] Open
Abstract
Despite strict pre- and post-transplantation screening, the incidence of new-onset diabetes after transplantation (NODAT) remains as high as 60%. This complication affects the risk of cardiovascular events and patient and graft survival rates. Thus, reducing the impact of NODAT could improve overall transplant success. The pathogenesis of NODAT is multifactorial, and both modifiable and nonmodifiable risk factors have been implicated. Monitoring and controlling the blood glucose profile, implementing multidisciplinary care, performing lifestyle modifications, using a modified immunosuppressive regimen, administering anti-metabolite agents, and taking a conventional antidiabetic approach may diminish the incidence of NODAT. In addition to these preventive strategies, inhibition of dipeptidyl peptidase-4 (DPP4) by the gliptin family of drugs has recently gained considerable interest as therapy for type 2 diabetes mellitus and NODAT. This review focuses on the role of DPP4 inhibitors and discusses recent literature regarding management of NODAT.
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Affiliation(s)
- Sun Woo Lim
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Zhe Jin
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
| | - Long Jin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jian Jin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
| | - Can Li
- Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, Yanji, China
- Correspondence to Can Li, M.D. Division of Nephrology, Department of Internal Medicine, Yanbian University Hospital, #1327 JuZi St., Yanji 133000, China Tel: +86-433-266-0065 Fax: +86-433-251-3610 E-mail:
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Abdel-Aziz O, Ayad MF, Tadros MM. Compatible validated spectrofluorimetric and spectrophotometric methods for determination of vildagliptin and saxagliptin by factorial design experiments. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2015; 140:229-240. [PMID: 25613694 DOI: 10.1016/j.saa.2014.12.102] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/08/2014] [Accepted: 12/28/2014] [Indexed: 06/04/2023]
Abstract
Simple, selective and reproducible spectrofluorimetric and spectrophotometric methods have been developed for the determination of vildagliptin and saxagliptin in bulk and their pharmaceutical dosage forms. The first proposed spectrofluorimetric method is based on the dansylation reaction of the amino group of vildagliptin with dansyl chloride to form a highly fluorescent product. The formed product was measured spectrofluorimetrically at 455 nm after excitation at 345 nm. Beer's law was obeyed in a concentration range of 100-600 μg ml(-1). The second proposed spectrophotometric method is based on the charge transfer complex of saxagliptin with tetrachloro-1,4-benzoquinone (p-chloranil). The formed charge transfer complex was measured spectrophotometrically at 530 nm. Beer's law was obeyed in a concentration range of 100-850 μg ml(-1). The third proposed spectrophotometric method is based on the condensation reaction of the primary amino group of saxagliptin with formaldehyde and acetyl acetone to form a yellow colored product known as Hantzsch reaction, measured at 342.5 nm. Beer's law was obeyed in a concentration range of 50-300 μg ml(-1). All the variables were studied to optimize the reactions' conditions using factorial design. The developed methods were validated and proved to be specific and accurate for quality control of vildagliptin and saxagliptin in their pharmaceutical dosage forms.
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Affiliation(s)
- Omar Abdel-Aziz
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt
| | - Miriam F Ayad
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt
| | - Mariam M Tadros
- Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
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Gault VA, Lennox R, Flatt PR. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes Obes Metab 2015; 17:403-13. [PMID: 25580570 DOI: 10.1111/dom.12432] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 12/17/2014] [Accepted: 12/31/2014] [Indexed: 12/25/2022]
Abstract
AIM To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice. METHODS High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed. RESULTS Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3β, superdioxide mutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered. CONCLUSION These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.
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Affiliation(s)
- V A Gault
- Diabetes Research Group, School of Biomedical Sciences, University of Ulster, Coleraine, UK
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Sensitivity-based analytical approaches to support human absolute bioavailability studies. Bioanalysis 2014; 6:497-504. [PMID: 24568352 DOI: 10.4155/bio.13.318] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The characterization of absolute bioavailability (BA) is useful for non-intravenous (iv.) formulations during drug development and is required by some health authorities. A study design of co-administrating an iv. isotopically labeled microdose with a therapeutic oral dose is a viable approach for the determination of human PK and has been accepted by regulatory agencies. The implementation of an iv.-microdose with oral therapeutic dose in absolute BA studies speeds up clinical development. In recent years, AMS to measure a radiolabeled microdose has been utilized to support several clinical absolute BA studies. An alternative approach for conducting microdose studies is using LC-MS/MS alone to quantitate both the iv. drug and the oral drug. Because both labeled and unlabeled drugs can be measured simultaneously with LC-MS/MS, it is cost effective. However, for compounds with high volume of distribution and/or poor LC-MS/MS response, AMS still provides a superior LLOQ. In this Perspective, we discuss a paradigm for selecting either an LC-MS/MS or AMS-based approach for generating concentration data in absolute BA studies dependent on the required sensitivity.
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Dejager S, Schweizer A. Incretin therapies in the management of patients with type 2 diabetes mellitus and renal impairment. Hosp Pract (1995) 2014; 40:7-21. [PMID: 22615074 DOI: 10.3810/hp.2012.04.965] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Renal impairment (RI) is common among patients with type 2 diabetes mellitus (T2DM), and these patients also experience an age-related decline in renal function. At the same time, treatment options are more limited and treatment is more complex, particularly in patients with moderate or severe RI due to contraindications, need for dose adjustment and/or regular monitoring, and side effects, such as fluid retention and hypoglycemia, which are a more serious concern in this patient population. Incretin therapies, consisting of the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are a promising new class of antihyperglycemic drugs. In the overall population, they improve glycemic control in a glucose-dependent manner and are not likely to cause hypoglycemia, representing a clear advantage in at-risk populations. Data regarding use of these agents in renally impaired patients have started to emerge, and the objective of this article is to provide an overview of the currently available data and the potential role of these novel agents in the management of patients with T2DM and RI. Data for the GLP-1 receptor agonists in patients with moderate or severe RI are still limited, with no trials dedicated to these populations currently published. In addition, their potential to cause gastrointestinal side effects may limit use in patients with RI due to the risk of dehydration and hypovolemia. The use of GLP-1 receptor agonists in patients with moderate or severe RI is therefore, at present, underlying caution and/or restrictions. On the other hand, data from specific trials in patients with moderate or severe RI are now becoming available for most of the DPP-4 inhibitors. These studies demonstrate good efficacy and tolerability of the DPP-4 inhibitors in patients with moderate or severe RI, thus opening a place for these therapies in the treatment of populations with T2DM and RI. Several of the DPP-4 inhibitors are already approved for use in patients with moderate or severe RI, including for those with end-stage renal disease. While discussing the advantages related to their common mechanism of action, this article also describes differences among the DPP-4 inhibitors (eg, related to their pharmacokinetic properties and the available clinical data). In conclusion, while initial data for these new therapies are promising, further experience is needed to fully assess the risk-benefit balance and clinical positioning of these agents in RI populations.
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Abdel-Ghany MF, Abdel-Aziz O, Ayad MF, Tadros MM. Stability-Indicating Liquid Chromatographic Method for Determination of Saxagliptin and Structure Elucidation of the Major Degradation Products Using LC-MS. J Chromatogr Sci 2014; 53:554-64. [DOI: 10.1093/chromsci/bmu084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Lenz EM, Martin S, Schmidt R, Morin PE, Smith R, Weston DJ, Bayrakdarian M. Reactive Metabolite Trapping Screens and Potential Pitfalls: Bioactivation of a Homomorpholine and Formation of an Unstable Thiazolidine Adduct. Chem Res Toxicol 2014; 27:968-80. [DOI: 10.1021/tx5000409] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Eva. M. Lenz
- DMPK
Department, Alderley Park, AstraZeneca UK Ltd., Macclesfield, Cheshire SK10 4TG, United Kingdom
| | - Scott Martin
- DMPK
Department, Alderley Park, AstraZeneca UK Ltd., Macclesfield, Cheshire SK10 4TG, United Kingdom
| | - Ralf Schmidt
- DMPK and Medicinal Chemistry Department, AstraZeneca R&D Montreal, St. Laurent, QC Canada H4S 1Z9
| | - Pierre-Emmanuel Morin
- DMPK and Medicinal Chemistry Department, AstraZeneca R&D Montreal, St. Laurent, QC Canada H4S 1Z9
| | - Robin Smith
- DMPK
Department, Alderley Park, AstraZeneca UK Ltd., Macclesfield, Cheshire SK10 4TG, United Kingdom
| | - Daniel J. Weston
- DMPK
Department, Alderley Park, AstraZeneca UK Ltd., Macclesfield, Cheshire SK10 4TG, United Kingdom
| | - Malken Bayrakdarian
- DMPK and Medicinal Chemistry Department, AstraZeneca R&D Montreal, St. Laurent, QC Canada H4S 1Z9
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Filippatos TD, Athyros VG, Elisaf MS. The pharmacokinetic considerations and adverse effects of DPP-4 inhibitors [corrected]. Expert Opin Drug Metab Toxicol 2014; 10:787-812. [PMID: 24746233 DOI: 10.1517/17425255.2014.907274] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a class of anti-hyperglycemic agents with proven efficacy in patients with type 2 diabetes mellitus (T2DM). AREAS COVERED This review considers the pharmacokinetic profile, adverse effects and drug interactions of DPP-4 inhibitors. DPP-4 inhibitors have certain differences in their structure, metabolism, route of elimination and selectivity for DPP-4 over structurally related enzymes, such as DPP-8/DPP-9. They have a low potential for drug interactions, with the exception of saxagliptin that is largely metabolized by cytochrome CYP3A4/A5. Reports of pancreatitis and pancreatic cancer have raised concerns regarding the safety of DPP-4 inhibitors and are under investigation. Post-marketing surveillance has revealed less common adverse effects, especially a number of skin- and immune-related adverse effects. These issues are covered in the present review. EXPERT OPINION DPP-4 inhibitors are useful and efficient drugs. DPP-4 inhibitors have similar mechanism of action and similar efficacy. However, DPP-4 inhibitors have certain differences in their pharmacokinetic properties that may be associated with different clinical effects and adverse event profiles. Although clinical trials indicated a favorable safety profile, post-marketing reports revealed certain safety aspects that need further investigation. Certainly, more research is needed to clarify if the differences among DPP-4 inhibitors could lead to a different clinical and safety profile.
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Affiliation(s)
- Theodosios D Filippatos
- Aristotle University of Thessaloniki, Hippokration Hospital, Medical School, Second Propedeutic Department of Internal Medicine , Thessaloniki , Greece
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Kim Y, Kim U, Kim IS, Lee SH, Lee J, Kim DH, Yoo HH. Absorption, distribution, metabolism and excretion of gemigliptin, a novel dipeptidyl peptidase IV inhibitor, in rats. Xenobiotica 2014; 44:627-34. [PMID: 24738939 DOI: 10.3109/00498254.2013.873156] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of (14)C-labeled gemigliptin to rats. 2. The (14)C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24 h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples. 3. The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).
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Affiliation(s)
- Yoon Kim
- Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University , Ansan , Republic of Korea
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Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol 2014; 118:1-18. [PMID: 24582776 DOI: 10.1016/j.pneurobio.2014.02.005] [Citation(s) in RCA: 176] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 02/09/2014] [Accepted: 02/20/2014] [Indexed: 12/13/2022]
Abstract
Insulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD.
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Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells. Eur J Pharmacol 2014; 727:8-14. [PMID: 24485890 DOI: 10.1016/j.ejphar.2014.01.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/26/2013] [Accepted: 01/09/2014] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus is associated with a decrease in bone quality and an increase in fracture incidence. Additionally, treatment with anti-diabetic drugs can either adversely or positively affect bone metabolism. In this study we evaluated: the effect of a 3-week oral treatment with saxagliptin on femoral microarchitecture in young male non-type-2-diabetic Sprague Dawley rats; and the in vitro effect of saxagliptin and/or fetal bovine serum (FBS), insulin or insulin-like growth factor-1 (IGF1), on the proliferation, differentiation (Runx2 and PPAR-gamma expression, type-1 collagen production, osteocalcin expression, mineralization) and extracellular-regulated kinase (ERK) activation, in bone marrow stromal cells (MSC) obtained from control (untreated) rats and in MC3T3E1 osteoblast-like cells. In vivo, oral saxagliptin treatment induced a significant decrease in the femoral osteocytic and osteoblastic density of metaphyseal trabecular bone and in the average height of the proximal cartilage growth plate; and an increase in osteoclastic tartrate-resistant acid phosphatase (TRAP) activity of the primary spongiosa. In vitro, saxagliptin inhibited FBS-, insulin- and IGF1-induced ERK phosphorylation and cell proliferation, in both MSC and MC3T3E1 preosteoblasts. In the absence of growth factors, saxagliptin had no effect on ERK activation or cell proliferation. In both MSC and MC3T3E1 cells, saxagliptin in the presence of FBS inhibited Runx2 and osteocalcin expression, type-1 collagen production and mineralization, while increasing PPAR-gamma expression. In conclusion, orally administered saxagliptin induced alterations in long-bone microarchitecture that could be related to its in vitro down-regulation of the ERK signaling pathway for insulin and IGF1 in MSC, thus decreasing the osteogenic potential of these cells.
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El-Bagary RI, Elkady EF, Ayoub BM. Development and validation of a reversed phase liquid chromatographic method for the determination of three Gliptins and Metformin in the presence of Metformin impurity (1-cyanoguanidine). ACTA ACUST UNITED AC 2013. [DOI: 10.5155/eurjchem.4.4.444-449.844] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Wanka L, Iqbal K, Schreiner PR. The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem Rev 2013; 113:3516-604. [PMID: 23432396 PMCID: PMC3650105 DOI: 10.1021/cr100264t] [Citation(s) in RCA: 452] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Lukas Wanka
- Institute of Organic Chemistry, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany; Fax +49(641)9934309
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA
| | - Khalid Iqbal
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA
| | - Peter R. Schreiner
- Institute of Organic Chemistry, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany; Fax +49(641)9934309
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Obach RS. Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacol Rev 2013; 65:578-640. [PMID: 23406671 DOI: 10.1124/pr.111.005439] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are converted to metabolites that can retain the intrinsic affinity of the parent drug for the pharmacological target. Drug metabolism redox reactions such as heteroatom dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations can yield active metabolites, and in rare cases even conjugation reactions can yield an active metabolite. To understand the contribution of an active metabolite to efficacy relative to the contribution of the parent drug, the target affinity, functional activity, plasma protein binding, membrane permeability, and pharmacokinetics of the active metabolite and parent drug must be known. Underlying pharmacokinetic principles and clearance concepts are used to describe the dispositional behavior of metabolites in vivo. A method to rapidly identify active metabolites in drug research is described. Finally, over 100 examples of drugs with active metabolites are discussed with regard to the importance of the metabolite(s) in efficacy and safety.
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Affiliation(s)
- R Scott Obach
- Pfizer Inc., Eastern Point Rd., Groton, CT 06340, USA.
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Noninsulin glucose-lowering agents for the treatment of patients on dialysis. Nat Rev Nephrol 2013; 9:147-53. [DOI: 10.1038/nrneph.2013.12] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Overcoming bioanalytical challenges in an Onglyza(®) intravenous [(14)C]microdose absolute bioavailability study with accelerator MS. Bioanalysis 2013; 4:1855-70. [PMID: 22943617 DOI: 10.4155/bio.12.171] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND An absolute bioavailability study that utilized an intravenous [(14)C]microdose was conducted for saxagliptin (Onglyza(®)), a marketed drug product for the treatment of Type 2 diabetes mellitus. Concentrations of [(14)C]saxagliptin were determined by accelerator MS (AMS) after protein precipitation, chromatographic separation by UPLC and analyte fraction collection. A series of investigative experiments were conducted to maximize the release of the drug from high-affinity receptors and nonspecific adsorption, and to determine a suitable quantitation range. RESULTS A technique-appropriate validation demonstrated the accuracy, precision, specificity, stability and recovery of the AMS methodology across the concentration range of 0.025 to 15.0 dpm/ml (disintegration per minute per milliliter), the equivalent of 1.91-1144 pg/ml. Based on the study sample analysis, the mean absolute bioavailability of saxagliptin was 50% in the eight subjects with a CV of 6.6%. Incurred sample reanalysis data fell well within acceptable limits. CONCLUSION This study demonstrated that the optimized sample pretreatment and chromatographic separation procedures were critical for the successful implementation of an UPLC plus AMS method for [(14)C]saxagliptin. The use of multiple-point standards are useful, particularly during method development and validation, to evaluate and correct for concentration-dependent recovery, if observed, and to monitor and control process loss and operational variations.
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Saxagliptin Improves Glucose Tolerance but not Survival in a Murine Model of Dilated Cardiomyopathy. Cardiovasc Endocrinol 2012; 1:74-82. [PMID: 23795310 DOI: 10.1097/xce.0b013e32835bfb24] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Glucagon-like peptide 1 (GLP-1) agonists improve myocardial function and insulin sensitivity in the setting of chronic heart failure. Endogenously produced GLP-1 peptide (7-36) is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) to the 9-36 peptide, which lacks anti-hyperglycemic activity. To elucidate the effect of increased endogenous GLP-1 during heart failure progression, the DPP4 inhibitor saxagliptin or vehicle was administered by daily oral gavage to female TG9 mice, a transgenic model of dilated cardiomyopathy, starting at day of life 42, just prior to the development of detectable contractile dysfunction. Saxagliptin treatment inhibited DPP4 activity >90% and increased GLP-1 levels 4-fold following a 2 gm/kg glucose load but did not affect fasting GLP-1 levels. There was no difference in food intake or body weight between groups. At 56 days of age, oral glucose tolerance was improved in saxagliptin-versus vehicle-treated animals (AUC0-120 1340 ± 46 and 1501 ± 43 min·mmol/L, respectively, p<0.015). In contrast to the effect of a GLP-1 agonist in TG9 mice, saxagliptin had no effect on survival (80.7 ± 4.3 days) compared to vehicle-treated mice (79.6 ± 3.6 days, p = 0.46). Taken together, these data indicate that improvement in glucose tolerance is not sufficient to improve survival. Future efforts to confirm these findings in additional models of heart failure are warranted.
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Harsha S, Attimard M, Khan TA, Nair AB, Aldhubiab BE, Sangi S, Shariff A. Design and formulation of mucoadhesive microspheres of sitagliptin. J Microencapsul 2012. [DOI: 10.3109/02652048.2012.720722] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Ali S, Fonseca V. Saxagliptin overview: special focus on safety and adverse effects. Expert Opin Drug Saf 2012; 12:103-9. [PMID: 23137182 DOI: 10.1517/14740338.2013.741584] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Saxagliptin (see drug summary box) is a glucose-lowering agent that belongs to the class of Dipeptidylpeptidase-4 (DDP-4) inhibitors used in the treatment of T2DM. Clinical efficacy of saxagliptin as single agent as well as in combination with other medications used for the treatment of T2DM has been well established in several randomized trials. Treatment with saxagliptin is effective, generally safe and well tolerated, apart from a small increase in the incidence of infections such as nasopharyngitis. Its use is not associated with increase risk of hypoglycemia and it is weight neutral. Saxagliptin can be used safely in renal failure (with dose adjustment) and in hepatic impairment. When saxagliptin is used in combination with a strong inhibitor of CYP3A4/A5, reduction in the daily dosage is recommended. AREAS COVERED This paper briefly discusses efficacy and pharmacokinetics of saxagliptin. The paper highlights in detail saxagliptin-associated adverse effects, drug interactions, its use in patients with renal and hepatic disease and long-term safety concerns. EXPERT OPINION Saxagliptin has comparable efficacy with other DPP-4 inhibitors. It is generally safe and well tolerated; however, it requires dose adjustment in renal disease as well as when used with drugs that are strong inhibitor or inducer of CYP3A4/A5 isoforms. Future safety questions regarding immune system and development of cancer still remain to be completely answered.
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Affiliation(s)
- Shamsa Ali
- Tulane University, Medicine, New Orleans 70112, USA.
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Dipeptidyl Peptidase-4 Inhibition With Saxagliptin Enhanced Nitric Oxide Release and Reduced Blood Pressure and sICAM-1 Levels in Hypertensive Rats. J Cardiovasc Pharmacol 2012; 60:467-73. [DOI: 10.1097/fjc.0b013e31826be204] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP4 inhibitors--from preclinical development to clinical research. Kidney Blood Press Res 2012; 36:65-84. [PMID: 22947920 DOI: 10.1159/000339028] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2012] [Indexed: 12/18/2022] Open
Abstract
Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure.
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Affiliation(s)
- Berthold Hocher
- Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
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