Involvement of sulfate conjugation and multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of garenoxacin in rats

In this study, the involvement of sulfate conjugation and drug efflux transporter multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of a new quinolone antimicrobial agent, garenoxacin, was investigated in Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBRs) lacking Mrp2. The disappearance of garenoxacin from plasma in female SD rats was significantly faster than that in male SD rats after a single intravenous injection of garenoxacin (5 mg/kg). The systemic clearance of garenoxacin in female rats was approximately threefold larger than that of male rats (2.43 ± 0.31 and 0.87 ± 0.06 l/h/kg, respectively), suggesting the existence of sex-related differences in the pharmacokinetics of garenoxacin. When rats received a constant-rate infusion of garenoxacin, the contribution of biliary and renal excretion of garenoxacin was small, and no significant difference in the biliary (CLBILE) clearance of garenoxacin was observed between male and female SD rats. The metabolic clearance [CLM (SULF)] of garenoxacin to garenoxacin sulfate conjugate (which is mainly excreted into the bile) in female SD rats was 8.5-fold larger than that in male SD rats (27.9 ± 2.94 and 3.28 ± 0.07 ml/h/kg, respectively). The CLBILE of garenoxacin was decreased in male and female EHBRs by approximately 50% compared with that in male and female SD rats. These results suggest that sulfate conjugation, but not Mrp2, is mainly involved in the sex-related differences in the pharmacokinetics of garenoxacin.