Vol. 282, Issue 1, 162-171, 1997

Carrier-Mediated Hepatic Uptake of Quinolone Antibiotics in the Rat

Hiroyuki Sasabe, Tetsuya Terasaki, Akira Tsuji and Yuichi Sugiyama

Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo Bunkyo-ku, Tokyo, 113, Japan (H.S., Y.S.); Faculty of Pharmaceutical Sciences, University of Tohoku, Aramaki aza-aoba, Aoba-ku, Sendai, Miyagi, 980-77, Japan (T.T.) and Faculty of Pharmaceutical Sciences, University of Kanazawa, 13-1, Takaramachi, Ishikawa, 920, Japan (A.T.)

The systemic clearance of many quinolone antibiotics is mainly via metabolism and urinary excretion; by contrast, biliary excretion is a major route of elimination for a new quinolone grepafloxacin (GPFX). Accordingly, we studied the hepatic uptake of GPFX because it is the first step in the drug's hepatobiliary transport. The hepatic uptake of GPFX in vivo after i.v. administration was found to approach the hepatic blood flow, suggesting the existence of an effective hepatic uptake mechanism. To clarify this transport mechanism, GPFX uptake by isolated rat hepatocytes was examined and found to consist of a saturable component (K_m 173 µM, V_max 6.96 nmol/min/mg) and a nonspecific diffusion component. The inhibition of GPFX uptake by ATP-depletors and a lack of effect after replacing Na⁺ with choline demonstrated that the uptake was an Na⁺-independent carrier-mediated active process. This uptake was inhibited by other quinolones and for lomefloxacin this was competitive in nature. Mutual inhibition studies were undertaken to investigate whether the transporter for GPFX might be the same as other transporters so far identified. GPFX inhibited the uptake of taurocholic acid, pravastatin (organic anion), cimetidine (organic cation) and ouabain (neutral steroid). However, GPFX uptake was not inhibited by these compounds. Confirmation that GPFX uptake is blood flow limited was obtained by extrapolation of the in vitro data based on mathematical modeling. In conclusion, the effective hepatic uptake of quinolone antibiotics are via carrier-mediated active transport, which is distinct from that involved in the transport of bile acids, organic anions, organic cations or neutral steroids.