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Vol. 284, Issue 3, 1033-1039, March 1998
Faculty of Pharmaceutical Sciences (H.S. and Y.S.), University of
Tokyo, Tokyo, Japan and
Faculty of Pharmaceutical Sciences (A.T.),
University of Kanazawa, Kanazawa, Ishikawa, Japan
Grepafloxacin (GPFX) has a comparatively greater hepatobiliary
transport than other quinolone antibiotics. The biliary excretion mechanism of GPFX was investigated in a series of in vivo
and in vitro studies with Sprague-Dawley rats and the mutant
strain Eisai-hyperbilirubinemia rats (EHBR), which have a hereditary defect in their bile canalicular multispecific organic anion transport system (cMOAT). The biliary excretion of the parent drug in EHBR was
38% of that in normal rats, whereas the 3-glucuronide, a main metabolite of GPFX, was scarcely excreted into the bile in EHBR. To
clarify the biliary excretion mechanism of GPFX, studies of uptake by
bile canalicular membrane vesicle (CMV) were performed. ATP dependence
was observed in the uptake of GPFX by CMV, although the extent was not
very marked, whereas no ATP-dependent uptake was observed by CMV
prepared from EHBR. An inhibition study of the ATP-dependent uptake of
the glutathione conjugate, 2,4-dinitrophenyl-S-glutathione (DNP-SG), a
typical substrate for cMOAT, was performed in order to differentiate
among the affinities of six quinolone antibiotics for this transporter.
All quinolone antibiotics inhibited the ATP-dependent uptake of DNP-SG
with different half-inhibition concentrations (IC50), and
GPFX had the lowest IC50 value. The uptake of
GPFX-glucuronide by CMV from normal rats showed a marked ATP
dependence, whereas there was little ATP-dependent uptake in EHBR. The
Km value (7.2 µM) for the higher-affinity
component of the glucuronide uptake was comparable to the
Ki value (9.2 µM) of the glucuronide in terms
of inhibition of the ATP-dependent uptake of DNP-SG, which indicates
that DNP-SG and the glucuronide may share the same transporter, cMOAT.
The Ki value of the glucuronide observed in this
inhibition was less than 1/200 that of the parent, which suggests that
the glucuronide had a much higher affinity than the parent drug. These
results lead us to conclude that at least a part of the GPFX transport
and a major part of its glucuronide transport across the bile
canalicular membrane are by a primary active transport mechanism
mediated by cMOAT.
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