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Drug Metabolism and Disposition Fast Forward
First published on January 12, 2009; DOI: 10.1124/dmd.108.024059

0090-9556/09/3704-841-846$20.00
DMD 37:841-846, 2009

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Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

Yiding Hu, Kathleen E. Sampson, Bruce R. Heyde, Kathy M. Mandrell, Na Li, Anup Zutshi, and Yurong Lai

Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri

Multidrug-resistant protein 2 (MRP2/ABCC2), expressed on the canalicular membrane of hepatocytes, mediates the secretion of conjugated or nonconjugated compounds into bile and plays an important role in physiology and drug elimination. A heterocyclic compound, BPCPU [1-(1-(4-bromophenyl)-3-carbamoyl-1H-pyrazol-4-yl) urea], which was metabolically stable in vitro in rat liver microsomes and freshly isolated rat hepatocytes, demonstrated a saturable nonlinear pharmacokinetic profile in the rat. Polarized efflux was observed for this compound in Caco-2 cells, with a low Km = 1.06 ± 0.06 µM. The Caco-2 efflux was dose-dependent and saturable. Coadministration of 25 µM MK571 ([3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid]), an MRP inhibitor, blocked the polarized efflux in Caco-2 cells. In contrast, this compound did not inhibit calcein efflux in MRP2 gene-transfected Madin-Darby canine kidney cells, suggesting that it is a substrate, not an inhibitor, of the MRP2/ABCC2 transporter. To investigate the mechanism for the nonlinear pharmacokinetics, bile duct-cannulated rats were used to obtain time profiles of plasma concentration, biliary, and urinary excretion after intravenous administration at various doses. The plasma clearance increased remarkably with decreased dose, from 1.5 ml/min/kg at 5 mg/kg to 14.9 ml/min/kg at 0.05 mg/kg. A dose-dependent biliary excretion also was observed. The results revealed that saturation of hepatobiliary secretion played a role in the dose-dependent changes in total body clearance and biliary clearance. Saturating concentrations of the Mrp2/Abcc2 substrate, BPCPU, causing decreased hepatobiliary clearance could be the major cause for the nonlinear pharmacokinetics observed in rats.

Address correspondence to: Dr. Yurong Lai, Pharmacokinetic, Dynamics, and Metabolism, Pfizer, Inc., St. Louis Laboratory, 700 Chesterfield Parkway West, Chesterfield, MO. E-mail: yurong.lai{at}pfizer.com






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