Pharmacokinetics of Clinafloxacin Enantiomers in Humans

Abstract

The pharmacokinetics of R‐clinafloxacin and S‐clinafloxacin enantiomers of the broad‐spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (± SD) bioavailability of R‐clinafloxacin was 87.5% ± 4.8% compared to 86.2% ± 5.8% for S‐clinafloxacin. The mean Cmax of each enantiomer was 1.19 μg/mL, with plasma concentrations of each enantiomer remaining above 0.1 μg/mL for at least 12 hours. No notable differences in the disposition of R‐clinafloxacin and S‐clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (± SD) t1/2 was 5.6 ± 0.3 hours and 5.7 ± 0.4 hours, plasma Cl was 329 ± 49 mL/min and 314 ± 45 mL/min, and Vdss was 138 ± 18 L and 134 ± 16 L for R‐ and S‐clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1‐week washout period between treatments. With probenecid coadministration, the increase in AUC0‐∞; was 75% and 83% for R‐clinafloxacin and was 71% and 75% for S‐clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R‐clinafloxacin and S‐clinafloxacin, although it had no stereo‐selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R‐ and S‐clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.