PT  - JOURNAL ARTICLE
AU  - Amit S. Kalgutkar
AU  - Bo Feng
AU  - Hang T. Nguyen
AU  - Kosea S. Frederick
AU  - Scott D. Campbell
AU  - Heather L. Hatch
AU  - Yi-An Bi
AU  - Diana C. Kazolias
AU  - Ralph E. Davidson
AU  - Rouchelle J. Mireles
AU  - David B. Duignan
AU  - Edna F. Choo
AU  - Sabrina X. Zhao
TI  - Role of Transporters in the Disposition of the Selective Phosphodiesterase-4 Inhibitor (+)-2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic Acid in Rat and Human
AID  - 10.1124/dmd.107.016162
DP  - 2007 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 2111--2118
VI  - 35
IP  - 11
4099  - http://dmd.aspetjournals.org/content/35/11/2111.short
4100  - http://dmd.aspetjournals.org/content/35/11/2111.full
SO  - Drug Metab Dispos2007 Nov 01; 35
AB  - 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 area under the curve) 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 (Km = 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 (Km = 12 μM) for Oatp1a4. The role of rat Mrp2 in the biliary excretion was also examined in 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. The American Society for Pharmacology and Experimental Therapeutics