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Carrier-Mediated Mechanism for the Biliary Excretion of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in Rats

Carrier-Mediated Mechanism for the Biliary Excretion of the Quinolone Antibiotic Grepafloxacin... Abstract 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 (IC 50 ), and GPFX had the lowest IC 50 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 K m value (7.2 μM) for the higher-affinity component of the glucuronide uptake was comparable to the K i 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 K i 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Pharmacology and Experimental Therapeutics Am. Soc for Pharma & Experimental Therapeutics

Carrier-Mediated Mechanism for the Biliary Excretion of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in Rats

Carrier-Mediated Mechanism for the Biliary Excretion of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in Rats

The Journal of Pharmacology and Experimental Therapeutics , Volume 284 (3): 1033 – Mar 1, 1998

Abstract

Abstract 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 (IC 50 ), and GPFX had the lowest IC 50 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 K m value (7.2 μM) for the higher-affinity component of the glucuronide uptake was comparable to the K i 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 K i 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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Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565
eISSN
1521-0103
Publisher site

Abstract

Abstract 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 (IC 50 ), and GPFX had the lowest IC 50 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 K m value (7.2 μM) for the higher-affinity component of the glucuronide uptake was comparable to the K i 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 K i 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.

Journal

The Journal of Pharmacology and Experimental TherapeuticsAm. Soc for Pharma & Experimental Therapeutics

Published: Mar 1, 1998

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