Smoking drug interaction studies represent a common approach for the clinical investigation of CYP1A2 induction. Despite this important role, they remain an "orphan topic" in the existing regulatory framework of drug interaction studies, and important methodological aspects remain unaddressed. The University of Washington Drug Interaction Database (DIDB) was used to systematically review the published literature on dedicated smoking pharmacokinetic interaction studies in healthy subjects (1990 to 2021, inclusive). Various methodological aspects of identified studies were reviewed. A total of 51 studies met all inclusion criteria and were included in the analysis. Our review revealed that methods applied in smoking interaction studies are heterogeneous and often fall short of established methodological standards of other interaction trials. Methodological deficiencies included incomplete description of study populations, poor definition and lack of objective confirmation of smoker and nonsmoker characteristics, under-representation of female subjects, small sample sizes, frequent lack of statistical sample size planning, frequent lack of use of existing markers of nicotine exposure and CYP1A2 activity measurements, and frequent lack of control of extrinsic CYP1A2 inducing or inhibiting factors. The frequent quality issues in the assessment and reporting of smoking interaction trials identified in this review call for a concerted effort in this area, if the results of these studies are meant to be followed by actionable decisions on dose optimization, when needed, for the effects of smoking on CYP1A2 victim drugs in smokers.

To identify prescription drugs that require dosage adjustment or monitoring in patients who quit smoking and to provide recommendations for dosage adjustment based on available evidence.

Health care providers are urged to facilitate smoking cessation for patients who smoke, but the effects of smoking cessation on the metabolism of some drugs is not routinely considered.

A comprehensive literature review.

The review was conducted in 2008 using a computerised drug interaction program and multiple PubMed and CINAHL searches to identify prescription drugs with clinically significant pharmacokinetic or pharmacodynamic changes caused by smoking cessation.

Although much of the evidence is case report, dosage adjustments are clearly indicated for warfarin, olanzapine, clozapine and theophylline since they are metabolised by cytochrome P450 CYP1A2 and also have narrow therapeutic ratios. Careful monitoring is recommended for other CYP1A2 metabolised drugs, including those for hypertension and Alzheimer's disease. For many affected drugs, smoking cessation reverses smoking-induced CYP1A2 hepatic enzyme levels to normal, increasing plasma concentrations in patients whose dose was established while smoking. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, nicotine replacement will not alter the effect.

The effects of smoking cessation on drugs metabolised by CYP1A2 have been under-appreciated by health care providers. Smoking cessation may increase plasma levels of some drugs to potentially toxic levels. Further research is warranted to clarify this effect.

When patients stop smoking, providers should carefully review prescribed drug regimens and adjust or monitor drugs whose metabolism is affected by smoking cessation. This is particularly important for patients who abruptly stop smoking due to hospitalisation and for older patients who are likely to be taking multiple medications.

Because the prevalence of smoking in the United States remains significantly high, it is important to determine a patient's smoking status and perform a complete medication history to assess for potential drug interactions with smoking. Tobacco smoke can increase the hepatic metabolism and can oppose the pharmacologic effects of certain drugs. This article reviews the clinically significant drug interactions, resulting primarily from the induction of cytochrome P450 enzymes by tobacco smoke, of which all acute and critical care providers need to be aware when making therapeutic decisions and recommendations.

The goal of this study was to evaluate the influence of congestive heart failure (CHF) on the clearance of mexiletine.

The mexiletine clearance/bioavailability (CL/F) ratio was estimated in 584 inpatients receiving mexiletine therapy. The study population consisted of 210 patients with CHF [CHF group; 116 inpatients with New York Heart Association (NYHA) class I-II (group NYHA I-II) CHF and 94 inpatients with NYHA class III-IV (group NYHA III-IV) CHF] and 374 inpatients without CHF (Non-CHF group). Serum levels of mexiletine were determined by high performance liquid chromatography (HPLC).

Mexiletine clearance was significantly lower in the CHF group when compared with the Non-CHF group (0.264+/-0.093 vs. 0.393+/-0.082 l/h/kg, mean+/-S.D., p<0.05). Further, the CL/F ratio was 50% lower in group NYHA III-IV when compared with the Non-CHF group, and the CL/F ratio tended to change in inverse proportion to NYHA class.

CHF status significantly affects mexiletine clearance. Therefore, dose adjustments and careful monitoring are likely required in CHF patients receiving mexiletine.

Glucuronidation is a major drug-metabolizing reaction in humans. A pharmacological effect of glucuronide metabolites is frequently neglected and the value of therapeutic drug monitoring has been questioned. However, this may not always be true.

In this review the impact of glucuronidation on therapeutic drug monitoring has been evaluated on the basis of a literature search and experience from the own laboratory.

The potential role of monitoring glucuronide metabolite concentrations to optimize therapeutic outcome is addressed on the basis of selected examples of drugs which are metabolized to biologically active/reactive glucuronides. Furthermore indirect effects of glucuronide metabolites on parent drug pharmacokinetics are presented. In addition, factors that may modulate the disposition of these metabolites (e.g. genetic polymorphisms, disease processes, age, and drug-drug interactions) are briefly mentioned and their relevance for the clinical situation is critically discussed.

Glucuronide metabolites can have indirect as well as direct pharmacological or toxicological effects. Although convincing evidence to support the introduction of glucuronide monitoring into clinical practice is currently missing, measurement of glucuronide concentrations may be advantageous in specific situations. If the glucuronide metabolite has an indirect effect on the pharmacokinetics of the parent compound, monitoring of the parent drug may be considered. Furthermore pharmacogenetic approaches considering uridine diphosphate (UDP) glucuronosyltransferases polymorphisms may become useful in the future to optimize therapy with drugs subject to glucuronidation.

Mexiletine is extensively metabolized in man, with less than 10% of the dose being excreted unchanged in urine. Clinical drug-drug interaction studies as well as in vitro drug metabolism studies suggest that CYP1A2, in addition to CYP2D6, is involved in the metabolism of mexiletine in man. Therefore, the objective of the study was to determine whether potential inhibition of CYP1A2 by the quinolone antibiotic agent ciprofloxacin would alter the stereoselective disposition of mexiletine. Nineteen healthy men (10 smokers and 9 nonsmokers) received a single 200-mg oral dose of racemic mexiletine hydrochloride on 2 occasions: once alone and once during concomitant administration of ciprofloxacin 750 mg BID (starting 3 days before and up to 2 days after the administration of mexiletine). Serial blood and urine samples were collected for 48 hours, and pharmacokinetic parameters were derived. Total clearances of R-(-)- and S-(+)-mexiletine were 42% and 63% higher in smokers compared with nonsmokers (P < 0.05). This observation is in agreement with increased clearance of mexiletine under conditions of increased CYP1A2 activity. On the other hand, ciprofloxacin administration only marginally decreased R-(-)- and S-(+)-mexiletine clearances (2 to 5 L/h; P < 0.05) secondary to a decrease in mexiletine nonrenal clearance. In conclusion, the increase in mexiletine nonrenal clearance in smokers and its decrease during the combined administration of ciprofloxacin confirm the role of CYP1A2 in the overall clearance of the drug. Nevertheless, results obtained in this study suggest that no major drug interaction is to be expected during the concomitant administration of ciprofloxacin and mexiletine in patients.

In vitro studies with human liver microsomes have suggested that the oxidative conversion of mexiletine (MX) to its metabolites is catalyzed by CYP2D6 and is significantly impaired in microsomes with the CYP2D6*10/*10 genotype. Therefore, we examined the influence of the CYP2D6*10 allele on MX pharmacokinetics in Japanese subjects.

Subjects with CYP2D6*1/*1 (group *1/*1; n=5), CYP2D6*10/*10 (group *10/*10; n=6) and CYP2D6*5/*10 (group *5/*10; n=4) genotypes received a single 200-mg dose of MX. Plasma and urinary levels of MX and its metabolites ( p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and N-hydroxymexiletine (NHM)) were determined by means of high-performance liquid chromatography.

Mean area under the concentration-time curve (AUC) and t(1/2) of MX were significantly ( P<0.05) higher in the CYP2D6*10/*5 group (AUC 11.23+/-3.05 micro g.h/ml; t(1/2) 15.5+/-3.2 h) than in the CYP2D6*1/*1 (AUC 5.53+/-1.01 micro g.h/ml; t(1/2) 8.1+/-1.6 h) and CYP2D6*10/*10 (AUC 7.32+/-2.36 micro g.h/ml; t(1/2) 10.8+/-2.8 h) groups, but there was no significant difference between the CYP2D6*1/*1 and CYP2D6*10/*10 groups. The maximum plasma concentration of MX was not significantly different among the three groups. The values of urinary excretion of PHM and HMM in the CYP2D6*1/*1 group were significantly ( P<0.05) higher than those in the CYP2D6*10/*10 and CYP2D6*5/*10 groups, but there was no significant difference in that of NHM among the three groups. Clearance of MX in the CYP2D6*5/*10 subjects was comparable to that in the poor metabolizers described previously.

The present findings demonstrated that carriers of the CYP2D6*10 allele showed a decreased clearance of MX. Subjects with CYP2D6*5/ *10 showed significantly ( P<0.05) increased plasma levels of MX, and homozygotes for CYP2D6*10 also showed an increase, although to a lesser extent. Thus, the CYP2D6*10 allele plays an important role in MX pharmacokinetics.

This paper reports a sensitive and specific enzyme-linked immunosorbent assay for determination of the antiarrhythmic drug mexiletine in human serum. Anti-mexiletine antibody was obtained by immunizing rabbits with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(epsilon-maleimidocaproyloxy)succinimide as a heterobifunctional coupling agent. Enzyme labeling of mexiletine with beta-D-galactosidase was performed using glutaraldehyde. In this assay, the mexiletine to be quantified is chemically modified by acetic anhydride allowed to compete with a mexiletine-beta-D-galactosidase conjugate for binding to a limited amount of an anti-mexiletine antibody which was used to coat the wells of a microtiter plate. Mexiletine concentrations lower than 80 ng/ml were measurable reproducibly by the enzyme-linked immunosorbent assay. This assay was specific for mexiletine and showed very slight cross-reactivity with its major metabolite, 2-hydroxymethylmexiletine (1.5%), but none with p-hydroxymexiletine. The values of serum mexiletine levels from 15 patients by this enzyme-linked immunosorbent assay were comparable with those measured by HPLC. There was a good correlation between the values determined by the two methods. The enzyme-linked immunosorbent assay should be a valuable tool in therapeutic drug monitoring and pharmacokinetic studies of mexiletine.

1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine. 2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 microm and 120 microm, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 microm and 3 microm, respectively (all p < 0.05 versus control). 3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r = 0.7827; R-(-)-enantiomer, r = 0.7034; S-(+)-enantiomer, r = 0.7495), CYP2E1 (S-(+)-enantiomer, r = 0.7057) and CYP1A2 (RS-mexiletine, r = 0.5334; S-(+)-enantiomer, r = 0.6035). 4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2B6) also appear to play a role in the N-oxidation of this drug.

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.

There are specific pharmacology issues related to women's unique physiology, including the hormonal changes that occur throughout their life span. Studies have shown alterations in drug metabolism in relation to phase of menstrual cycle, during pregnancy, or after menopause. In the brain, hormones can alter the response to drugs through various mechanisms. Estrogen and other compounds can bind to the estrogen receptor and modulate a wide range of activities within the cell. In addition, animal studies have demonstrated sexual dimorphism in the brain in terms of both the type of response to estrogen and the response as related to timing of administration. Many normal physiological changes that occur during pregnancy can affect pharmacokinetics and pharmacodynamics. These changes during pregnancy are dramatic rises in levels of estrogen and progesterone, increases in maternal blood volume, altered protein binding resulting from a drop in albumin levels, and a rise in levels of other plasma proteins. The field of chronobiology offers a way to study these changes in biological functions. Chronopharmacology is the study of how biological rhythms, particularly 24-hour, menstrual cycle, and annual rhythms, impact the pharmacokinetics and pharmacodynamics of drugs as a function of their timing. Chronopharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of medicines according to the time of day, menstrual cycle, or year. In addition to applying chronobiology to the study of drugs used in women, new technologies were addressed from computer modeling, pharmacogenetics (genetics of the response to drugs), and in vivo drug metabolism studies.

Amiodarone has pharmacokinetic interactions with various therapeutic agents, including phenytoin, flecainide, and cyclosporine. Mexiletine is metabolized by CYP2D6 and CYP1A2. The objective of this study is to evaluate the effect of amiodarone on the pharmacokinetics of mexiletine through its inhibition of various cytochrome P450 (CYP) subtypes. In a series of 181 inpatients with supraventricular tachyarrhythmias, 26 inpatients received mexiletine and amiodarone therapy (MEX + AMD group), and the others received mexiletine therapy (MEX group). In 10 inpatients of the MEX + AMD group, the mexiletine clearance (CL(MEX)/F) before and after coadministration of amiodarone was compared. CL(MEX)/F was also compared in the MEX and MEX + AMD groups after the start of amiodarone therapy. Serum mexiletine, amiodarone, and desethylamiodarone concentrations were measured by an HPLC method. The CL(MEX)/F was estimated by the Bayesian method using population pharmacokinetic analysis. There was no significant difference in CL(MEX)/F before and after 1-month coadministration of amiodarone in 10 inpatients of the MEX + AMD group. Although serum amiodarone and desethylamiodarone concentrations gradually increased with time after the start of amiodarone therapy in these patients, CL(MEX)/F showed no change at 3 and 5 months after the start of amiodarone therapy. There was no significant difference in CL(MEX)/F of the MEX group and the MEX + AMD group. The results suggest that the pharmacokinetics of mexiletine is not affected by amiodarone in patients with cardiac arrhythmias.

To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition.

Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC.

Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed.

The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.

Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed following oral administration with a bioavailability of about 90%. Peak plasma concentrations following oral administration occur within 1 to 4 hours and a linear relationship between dose and plasma concentration is observed in the dose range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is eliminated slowly in humans (with an elimination half-life of 10 hours). It undergoes stereoselective disposition caused by extensive metabolism. Eleven metabolites of mexiletine are presently known, but none of these metabolites possesses any pharmacological activity. The major metabolites are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N-hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine and m-hydroxy-mexiletine is genetically determined and cosegregates with polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity. On the other hand, CYP1A2 seems to be implicated in the N-oxidation of mexiletine. Various physiological, pathological, pharmacological and environmental factors influence the disposition of mexiletine. Myocardial infarction, opioid analgesics, atropine and antacids slow the rate of absorption, whereas metoclopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette smoking significantly enhance the rate of elimination of mexiletine, whereas ciprofloxacin, propafenone and liver cirrhosis decrease it. Cimetidine, ranitidine, fluconazole and omeprazole do not modify the disposition of mexiletine. Conversely, mexiletine is known to alter the disposition of other drugs, such as caffeine and theophylline. Factors affecting the elimination of mexiletine may be clinically important and dosage adjustments are often necessary.

Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens. Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1, CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking, CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone. In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with beta-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine. The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.

Caffeine consumption is extensive in industrialized countries and its role in drug-drug interactions is often overlooked. CYP1A2, the major cytochrome P450 isoform involved in the metabolism of caffeine, has also been implicated in the formation of N-hydroxymexiletine, the major metabolite of mexiletine. Therefore, the objective of this study was to assess the effects of a clinically relevant dosage of caffeine on the stereoselective disposition of mexiletine. Fourteen healthy volunteers--10 extensive metabolizers (EMs) and 4 poor metabolizers (PMs) of CYP2D6--received a single 200 mg oral dose of racemic mexiletine hydrochloride on two occasions (1 week apart): once by itself and once during administration of caffeine (100 mg four times daily). Serial blood and urine samples were collected and pharmacokinetic parameters were estimated. Although the total clearance of mexiletine was not significantly altered by the coadministration of caffeine in EMs and PMs, a stereoselective decrease (16% in EMs and 14% in PMs) in the urinary recovery of N-hydroxymexiletine from the R-(-)-enantiomer was observed. Also, the partial metabolic clearance of R-(-)-mexiletine to N-hydroxymexiletine glucuronide was reduced from 126 +/- 48 mL/min to 106 +/- 32 mL/min and 152.6 (73.4-196.2) mL/min to 109 (77-127) mL/min by the coadministration of caffeine in EMs and PMs, respectively. Consequently, the R/S ratio for urinary recovery and the partial metabolic clearance of mexiletine to N-hydroxymexiletine were 28% lower during the coadministration of caffeine. In conclusion, data obtained in this study indicate that coadministration of caffeine does not lead to clinically significant changes in mexiletine plasma concentrations. However, results obtained suggest that CYP1A2 is involved in the formation of N-hydroxymexiletine.

Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease.

Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.

Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism.

Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF).

Mexiletine p- and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p- and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1'-hydroxylase activity (r = 0.907, P < 0.001 and r = 0.886, P < 0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p- and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYPIA2 to both mexiletine p- and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the Km values of the expressed CYP1A2 (approximately 15 microM) were almost identical with those of the expressed CYP2D6 (approximately 22 microM) and human liver microsomes.

Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.

The aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2.

The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2.

Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 microM, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC50 >1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC50 values ranging from 86 to 704 microM. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2.

These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.

The enantiomers of mexiletine and four of its hydroxylated metabolites were directly separated by capillary gas chromatography using a heptakis(6-O-tert-butyl-dimethylsilyl-2,3-di-O-methyl)-beta- cyclodextrin column. The method was applied to the analysis of urine samples from cancer patients who were treated with racemic mexiletine as part of a study of the use of mexiletine in the relief of neuropathic pain. Samples analyzed before and after deconjugation of the urine with beta-glucuronidase/arylsulfatase showed a high stereoselectivity in the formation and conjugation of these compounds.

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 +/- 6.9 (mean +/- s.d.) to 33.7 +/- 5.0 ml kg-1 h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 +/- 2.5 to 10.4 +/- 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of mexiletine and its four hydroxylated metabolites in human serum. The method involves a single-step extraction of mexiletine, hydroxymethylmexiletine, p-hydroxymexiletine and their corresponding alcohols with diisopropyl ether-dichloromethane-propan-2-ol (2.5:1.5:0.5, v/v). Separation of the compounds on a deactivated Supelcosil LC8-DB column is accomplished by high-performance liquid chromatography with ultraviolet detection at 203 nm. Overall the recovery of each compound is reproducible and greater than 75%. The lower limit of detection is 2 ng/ml for mexiletine and its metabolites. The application of the method is shown by measuring the concentrations in serum of mexiletine and its metabolites over 24 h in a healthy volunteer after a single intravenous injection of the drug and by monitoring serum concentrations in patients receiving long-term treatment by mouth of the drug.

1. The relationship between the metabolism of the antiarrhythmic drug mexiletine and the debrisoquine/sparteine-type polymorphism was studied in vitro, using microsomes from six human livers, and in vivo, in nine healthy drug-free volunteers with wide variation in their ability to hydroxylate debrisoquine. 2. There was a strong and similar correlation between the formation rate of both major mexiletine metabolites, p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), and the high affinity component of dextromethorphan O-demethylase activity in human liver microsomes (rs = 0.94; P less than 0.01). 3. There were marked interindividual differences in the amounts of PHM and HMM excreted in the urine over 48 h after a single 200 mg oral dose of mexiletine hydrochloride. Recoveries of both metabolites were correlated inversely with the debrisoquine/4-hydroxydebrisoquine (D/HD) urinary metabolic ratio (rs = -0.83; P = 0.006 and rs = -0.85; P = 0.004, respectively) and were lower in poor metabolisers of debrisoquine (PM) than in extensive metabolisers (EM). Moreover, PM had the highest values of mexiletine/PHM and mexiletine/HMM urinary ratios. In addition, there was a strong correlation between these two indices of mexiletine hydroxylation and the D/HD metabolic ratios (rs = 0.92; P = 0.001 and rs = 0.90; P = 0.001, respectively). 4. After mexiletine pretreatment, the values for D/HD ratio were significantly increased in EM while corresponding values in PM were similar. 5. These findings are in accordance with previous in vitro data suggesting that PHM and HMM formation is predominantly catalyzed by the genetically variable human liver cytochrome P450IID6 isoenzyme responsible for the debrisoquine/sparteine-type polymorphism of drug oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(-)- and S-(+)-mexiletine were resolved with an optical purity greater than 98% (yield approximately 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7-30 days after coronary ligation. R-(-)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0.5 mg kg-1, 1 after 8 mg kg-1); two animals died after 1 and 8 mg kg-1, respectively; one remained unchanged even at the highest dosage (16 mg kg-1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg-1); two died after 4 and 8 mg kg-1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg-1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0.5-16.0 mg kg-1). These results suggest that R-(-)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.

The optimisation of antiarrhythmic drug therapy is dependent on the definitions and methods of short term efficacy testing and the characteristics of those drugs used for rhythm disturbances. The choice of an initial antiarrhythmic drug dosage is highly empirical, and will remain so until the measurement of free concentrations, enantiomeric fractions and genetic phenotyping becomes routine. However, the clinician can devise an efficient initial dosage for efficacy testing procedures based on pharmacokinetic principles and disposition variables in the literature. In this regard, a nomogram for commonly used agents and dosages was constructed and is offered as a guide to accomplish this goal. Verification of the accuracy and usefulness of this nomogram in a prospective manner in patients with symptomatic tachyarrhythmias is still required. On a long term basis, dosage regimens can be modified by the use of pharmacokinetic principles and patient-specific target concentrations, in accordance with the methods used to monitor arrhythmia recurrence and drug-related side effects.

Glucuronidation is a major metabolic pathway for a large number of drugs in humans. Conjugation of drugs and other chemicals with glucuronic acid is catalyzed by the multigene UDP-glucuronosyltransferase family. It is believed that a number (unspecified at present) of glucuronosyltransferase isozymes, which probably differ in terms of substrate specificity and regulation, contribute to drug glucuronidation. Factors known to influence the pharmacokinetics of glucuronidated drugs in man, presumably via an effect on specific glucuronosyltransferases, include age (especially the neonatal period), cigarette smoking, diet, certain disease states, coadministered drugs, ethnicity, genetics and hormonal effects.

Urinary elimination of unchanged mexiletine, p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and mexiletine N-glucuronide conjugate (MGC) was investigated before and after treatment with quinidine. All subjects were phenotyped as extensive metabolizers for debrisoquine oxidation. The total recovery of mexiletine and metabolites was significantly reduced after quinidine pretreatment. It is concluded that pretreatment with a very low dose of quinidine inhibits markedly the elimination of both major mexiletine metabolites (PHM and HMM) and likely decreases the overall elimination of mexiletine. That should lead to changes in mexiletine disposition and have clinical consequences during combination therapy with both drugs.

As a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals. In the dosage range 600 to 900 mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis. Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.

Mexiletine is a Class IB antiarrhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours. The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hemodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.

The cytochrome P-450dbl isozyme (P-450bdl) is responsible for the genetic sparteine-debrisoquine type polymorphism of drug oxidation in humans. To investigate the relationship between mexiletine oxidation and the activity of this isozyme, cross-inhibition studies were performed in human liver microsomes with mexiletine and dextromethorphan, a prototype substrate for P-450dbl. The formation of hydroxymethylmexiletine and p-hydroxymexiletine, two major mexiletine metabolites, was competitively inhibited by dextromethorphan. Mexiletine competitively inhibited the high affinity component of dextromethorphan O-demethylation. In addition, there was a good agreement between the apparent Km values for the formation of both mexiletine metabolites and the high affinity component of dextromethorphan O-demethylation and their respective apparent Ki values. Several drugs were tested for their ability to inhibit mexiletine oxidation. Quinidine, quinine, propafenone, oxprenolol, propranolol, ajmaline, desipramine, imipramine, chlorpromazine and amitryptiline were competitive inhibitors for the formation of hydroxymethylmexiletine and p-hydroxymexiletine as for prototype reactions of the sparteine-debrisoquine type polymorphism. Amobarbital, valproic acid, ethosuximide, caffeine, theophylline, disopyramide and phenytoin, known to be non-inhibitors of P-450dbl activity, were found not to inhibit the formation of these mexiletine metabolites. Moreover, the formation of both metabolites was strongly inhibited by an antiserum containing anti-liver/kidney microsomes antibodies type I (anti-LKMI) directed against P-450dbl. These data suggest that the formation of two major metabolites of mexiletine is predominantly catalysed by the genetically variable human liver P-450dbl.

The effect of advancing age on the kinetics of the antiarrhythmic agent mexiletine was studied by comparing various kinetic parameters calculated after administration of a single oral dose of mexiletine hydrochloride to seven elderly and eight young healthy volunteers. The rate of absorption of the drug from the gastrointestinal tract was significantly slower in the elderly (1.37 +/- 0.51 hr-1) than in the young group (2.25 +/- 0.79 hr-1). The mean values for elimination half-life and oral clearance were 12.3 +/- 3.7 hr and 10.3 +/- 5.4 mL/min/kg respectively in the young group and 14.4 +/- 4.5 hr and 8.5 +/- 2.9 mL/min/kg respectively in the elderly group. Neither of these parameters was significantly different between the two groups. The amount of mexiletine eliminated in urine up to 48 hours postdose was identical in both groups and represented less than 5% of the administered dose. It is concluded that the age-related modifications in the kinetics of mexiletine are not clinically important during chronic administration of the drug.

A simple high-performance liquid chromatographic assay, using fluorescence detection, is described for determining simultaneously the production of the two major hydroxylated metabolites of mexiletine in human liver microsomes. The detection limits of hydroxymethylmexiletine and p-hydroxymexiletine are 0.35 and 0.08 nmol/ml, respectively. The assay is specific, reproducible and allows the simultaneous kinetic characterization of the reactions in small amounts of liver tissue. The assay may be used to acquire a better knowledge of the kinetic behaviour of mexiletine and of its metabolites, and to investigate if the large inter-individual variations of the mexiletine pharmacokinetics are of metabolic origin, due to variations of its hydroxylation processes.

1. The effects of caffeine ingestion and cigarette smoking on caffeine and antipyrine pharmacokinetics were studied using normal subjects as their own controls before and after cessation of smoking in an attempt to minimize genetic and other environmental influences. 2. Moderate caffeine ingestion had no inducing effect on caffeine or antipyrine clearance. 3. Cessation of cigarette smoking significantly reduced clearance of caffeine and antipyrine. 4. These results demonstrate that cigarette smoking significantly affects caffeine pharmacokinetics and this may contribute to the variable results for caffeine kinetics found in patients with liver disease.

The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 +/- 0.12 (s.d.) and 0.80 +/- 0.21, respectively. Urinary excretion of mexiletine conjugates consisted mainly of the R-(-)-enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 +/- 3.10. Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 +/- 0.48 and the renal clearance of the R-(-)-enantiomer was significantly higher (P less than 0.02) than that of the S-(+)-enantiomer.