Fluoroquinolones (FQs) exist as charged molecules in blood and urine making their absorption, distribution, and elimination likely to be influenced by active transport mechanisms. Greater understanding of in vivo FQ clearance mechanisms should help improve the predictability of drug-drug interactions, enhance the clinical safety and efficacy, and aid future novel drug design strategies.

The authors present an overview of FQ development and associated drug-drug interactions, followed by systematic quantitative review of the physicochemical and in vivo pharmacokinetic properties for 15 representative FQs using historical clinical literature. These results were correlated with in vitro studies implicating drug transporters in FQ clearance to link clinical and in vitro evidence supporting the contribution of drug transport mechanisms to FQ disposition. Specific transporters likely to handle FQs in human renal proximal tubule cells are also identified.

Renal handling, that is, tubular secretion and reabsorption, appears to be the main determinant of FQ plasma half-life, clinical duration of action, and drug-drug interactions. Due to their zwitterionic nature, FQs are likely to interact with organic anion and cation transporters within the solute carrier (SLC) superfamily, including OAT1, OAT3, OCT2, OCTN1, OCTN2, MATE1, and MATE2. The ATP-binding cassette (ABC) transporters MDR1, MRP2, MRP4, and BCRP also may interact with FQs.

This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL(cr)) > 80 mL/min, CL(cr) < 30 mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600-mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3 h before HD (phase 1) and immediately after HD (phase 2).

Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed.

Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration-time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 +/- 7 h vs 14.4 +/- 3 h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5-11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated.

Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.

The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of grepafloxacin and levofloxacin in vivo. Plasma concentrations of grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of grepafloxacin was decreased to 33% of the control, and the bioavailability of grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of grepafloxacin in mdr1a/1b (-/-) mice, which lack mdr1-type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (-/-) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of grepafloxacin. In conclusion, our results indicated that P-glycoprotein mediated the intestinal secretion of grepafloxacin and limited the bioavailability of this drug in vivo.

The utility of the fluoroquinolone class of antibiotics is rapidly expanding due to their favourable pharmacokinetic profile and the continuing development of new compounds. These agents are often used for indications not successfully treated with other orally available antimicrobials in the past, or for 'step-down' therapy in patients originally treated with intravenous agents. As the usage of these agents expands for serious systemic infections, knowledge of absorptive interactions with fluoroquinolones becomes paramount. Fluoroquinolones are often utilised in dosages and against modestly susceptible pathogens which allow a narrow margin for acceptable decreases in bioavailability. Chelation interactions with multivalent cations can result in inactivation of the fluoroquinolone with ramifications in vitro and in vivo. Chelation interactions have been reported to occur in between 22 and 76% of patients prescribed fluoroquinolones. Concurrent administration of magnesium-aluminum antacids and sucralfate has the greatest effect on the bioavailability of quinolones followed by iron, calcium and zinc. Spacing doses of fluoroquinolones and interactants has been suggested as a method of ensuring adequate quinolone absorption, but this can make optimal administration of the cation interactant difficult, if not impossible.

A multicentre study was conducted to determine whether liver impairment would alter the pharmacokinetics of temafloxacin, a new fluoroquinolone antimicrobial agent. 16 patients with cirrhosis and 12 healthy volunteers (the control group) received a single oral 600mg dose of temafloxacin. Blood and urine were sampled at frequent intervals after drug administration and assayed by high performance liquid chromatography. The mean age of patients with liver impairment was greater than that of the control group; they also had a lower creatinine clearance and urine output. There was no difference between the groups in either the peak plasma temafloxacin concentration or the time to reach peak concentration. However, the volume of distribution and elimination rate constant of temafloxacin were significantly lower in the group with liver impairment, as were total temafloxacin clearance, renal clearance, and the ratio of renal:creatinine clearance. Nonrenal clearance was similar in patients and controls. Creatinine clearance and urine output were found to account for most of the intersubject variability in total clearance as determined by multiple linear regression analysis. Because the altered temafloxacin pharmacokinetics appear to be primarily due to impaired renal function, this should be the main determinant of temafloxacin dosage in patients with liver disease.

Four multiple dose studies involving 102 healthy volunteers were reviewed to determine the sources of intersubject variability in the pharmacokinetics of temafloxacin. As a result of the preferential distribution of temafloxacin into muscle, liver and kidney compared with adipose tissue, the best anthropometric explanatory variable was found to be lean body mass, rather than total body mass or body surface area. Single dose studies have confirmed that the distribution volume of temafloxacin is smaller in subjects in whom the lean body mass:total body mass ratio is low, notably in females, the elderly, and those with hepatic impairment. Average creatinine clearance for the volunteers included in this analysis was normal (109 +/- 29 ml/min), and renal function was only a marginally significant covariate; however, renal clearance accounts for 60 to 70% of total clearance (CLT) and has been shown to be a major factor in the elderly, as well as in patients with renal or hepatic impairment. Since temafloxacin is partially reabsorbed renally, urine flow rate was found to be a potentially important secondary factor. Overall, the pharmacokinetics of temafloxacin are essentially linear, with steady-state plasma concentrations at trough (Cssmin) and 2h postdose (Css2h) averaging slightly more than 0.5 and 1.0 mg/L per 100mg administered every (q) 12h. For example, mean Cssmin and peak steady-state plasma concentration (Cssmax) values after administration of temafloxacin 600mg q12h were 3.3 +/- 1.1 and 6.2 +/- 1.8 mg/L, respectively. Total apparent clearance (CLT/F) and the terminal elimination half-life (t1/2) averaged 11 L/h (184 ml/min) per 55kg lean body mass and 8.4h, respectively. Considering that the data reviewed came from 4 studies with doses ranging from 100 to 800mg q12h, the intersubject coefficients of variation were low for an orally administered drug, ranging from 15.4% for t1/2, 20.6% for Css2h, 21.2% for CLT/F and 25% for Cssmin.

Temafloxacin is a new antibacterial agent of the fluoroquinolone group. In comparison with ciprofloxacin, the current leading quinolone, temafloxacin shows higher and longer lasting plasma concentrations after equivalent doses due to an almost complete gastrointestinal absorption and a lower total clearance. Temafloxacin absorption is little influenced by food intake. Concomitant administration of antacids should be avoided; a time interval of at least 2 hours should elapse between intake of either quinolone and an antacid. Both quinolones are excreted mainly by the kidney. They differ in tubular secretion, which is high for ciprofloxacin and low for temafloxacin. The overall nonrenal elimination is similar for both compounds. Ciprofloxacin has a slightly higher extent of metabolism, while temafloxacin probably has a higher transintestinal elimination. The biliary excretion of both compounds is in the same range. The longer half-life of temafloxacin enables a once-daily dose regimen, whereas the usual recommended dosage of ciprofloxacin is twice daily. For both quinolones the apparent volumes of distribution per body weight are significantly above unity, indicating good tissue penetration with intracellular uptake. The concentrations in the extracellular fluids are directly related to the corresponding plasma concentrations. The penetration of temafloxacin into the body fluids investigated--tears, nasal secretion, saliva, sweat, prostatic and seminal fluid--in general exceeds that of ciprofloxacin (with the exception of seminal fluid). Unlike ciprofloxacin, there is no drug interaction with methylxanthines. Comparative clinical studies reflecting the complex interrelating factors of host and pathogens are needed to demonstrate the significance of the pharmacokinetic differences between temafloxacin and ciprofloxacin.

Temafloxacin (6-fluoro-7-piperazino-4-quinolone) is a new fluoroquinolone with a 7-8 hour half-life and rapid gastrointestinal absorption. These characteristics make it an ideal antimicrobial for once- or twice-daily oral dosing. With the exception of the central nervous system (CNS), temafloxacin has excellent tissue and body fluid penetration and concentration. Temafloxacin has broad antimicrobial activity against gram-positive and gram-negative bacteria, including improved in vitro activity against Streptococcus pneumoniae, Mycoplasma hominis, and anaerobic bacteria, including Bacteroides fragilis. Temafloxacin is as effective as beta-lactam therapy and superior to ciprofloxacin in the treatment of S. pneumoniae lower respiratory infections. It has been clinically effective when given in a short 3-day regimen for the treatment of uncomplicated urinary tract infections. Multiple clinical trials indicate that temafloxacin is also clinically effective, well tolerated, and safe for use in adult patients for the treatment of other lower respiratory tract, genitourinary tract, and skin and skin-structure infections.