Received for publication April 5, 2007.
Revised August 3, 2007.
Accepted for publication August 6, 2007.

Role of Transporters in the Disposition of the Selective Phosphodiesterase-4 Inhibitor (+)-2-[4-({[2-Benzo[1,3]dioxol-5-oxy)pyridine-3-carbonyl]-amino]methyl)-3-fluorophenoxy]propionic acid in Rat and Human

Abstract

The role of transporters in the disposition of (+)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid (CP-671,305), an orally active inhibitor of phosphodiesterase-4 was examined. In bile-duct exteriorized rats, a 7.4-fold decrease in the half-life of CP-671,305 was observed implicating enterohepatic recirculation. Statistically significant differences in CP-671,305 pharmacokinetics (clearance and AUC) were discernible in cyclosporin A- or rifampicin-pretreated rats. Considering that cyclosporin A and rifampicin inhibit multiple uptake/efflux transporters, the interactions of CP-671,305 with major human hepatic drug transporters, multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistant protein (BCRP) and organic anion-transporting polypeptide (OATPs) were evaluated in vitro. CP-671,305 was identified as a substrate of MRP2 and BCRP, but not MDR1. CP-671,305 was a substrate of human OATP2B1 with a high affinity (K_m=4 µM), but not a substrate for human OATP1B1 or OATP1B3. Consistent with these results, examination of hepatobiliary transport of CP-671,305 in hepatocytes indicated active uptake followed by efflux into bile canaliculi. Upon examination as a substrate for major rat hepatic Oatps, CP-671,305 displayed high affinity (K_m=12µM) for Oatp1a4. The role of rat Mrp2 in the biliary excretion was also examined in TR- (Mrp2-deficient) rats. The observations that CP-671,305 pharmacokinetics were largely unaltered suggested that compromised biliary clearance of CP-671,305 was compensated by increased urinary clearance. Overall, these studies suggest that hepatic transporters play an important role in the disposition and clearance of CP-671,305 in rat and human, and as such these studies should aid in the design of clinical drug-drug interaction studies.

Key words: drug-drug interactions, hepatobiliary disposition, hepatobiliary transport, hepatocytes, transporters

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