PT  - JOURNAL ARTICLE
AU  - Yiding Hu
AU  - Kathleen E. Sampson
AU  - Bruce R. Heyde
AU  - Kathy M. Mandrell
AU  - Na Li
AU  - Anup Zutshi
AU  - Yurong Lai
TI  - Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration
AID  - 10.1124/dmd.108.024059
DP  - 2009 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 841--846
VI  - 37
IP  - 4
4099  - http://dmd.aspetjournals.org/content/37/4/841.short
4100  - http://dmd.aspetjournals.org/content/37/4/841.full
SO  - Drug Metab Dispos2009 Apr 01; 37
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics