Saturation of multidrug-resistant protein 2 (mrp2/abcc2)-mediated hepatobiliary secretion: nonlinear pharmacokinetics of a heterocyclic compound in rats after intravenous bolus administration.
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 K(m) = 1.06 +/- 0.06 microM. The Caco-2 efflux was dose-dependent and saturable. Coadministration of 25 microM 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.
Hu
Yiding
Y
Pharmacokinetic, Dynamics, and Metabolism, Pfizer, Inc., St. Louis Laboratory, 700 Chesterfield Parkway West, Chesterfield, MO, USA.
Sampson
Kathleen E
KE
Heyde
Bruce R
BR
Mandrell
Kathy M
KM
Li
Na
N
Zutshi
Anup
A
Lai
Yurong
Y
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001659:Biliary Tract / Q000502:physiology*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000089762:Multidrug Resistance-Associated Protein 2; D011422:Propionates; D011804:Quinolines; C059141:verlukast