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Vol. 282, Issue 1, 162-171, 1997
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 (Km
173 µM, Vmax 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.
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