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

• Published in: Drug metabolism and disposition Vol. 35; no. 11; pp. 2111 - 2118
• Main Authors: KALGUTKAR, Amit S, BO FENG, DUIGNAN, David B, CHOO, Edna F, ZHAO, Sabrina X, NGUYEN, Hang T, FREDERICK, Kosea S, CAMPBELL, Scott D, HATCH, Heather L, BI, Yi-An, KAZOLIAS, Diana C, DAVIDSON, Ralph E, MIRELES, Rouchelle J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.11.2007
• Subjects: Animals; ATP Binding Cassette Transporter, Sub-Family B; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bile - metabolism; Biological and medical sciences; Cell Line; CHO Cells; Cricetinae; Cricetulus; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; Male; Medical sciences; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Molecular Structure; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Independent - genetics; Organic Anion Transporters, Sodium-Independent - metabolism; Pharmacology. Drug treatments; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - metabolism; Phosphodiesterase Inhibitors - pharmacokinetics; Propionates - chemistry; Propionates - metabolism; Propionates - pharmacokinetics; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacokinetics; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Rats, Wistar; Transfection; Human; Phosphodiesterase inhibitor; Carbonyl compounds; Vertebrata; Mammalia; Rat; Phosphodiesterase 4 inhibitor; Animal; Propionic acid; Rodentia; Pharmacokinetics; Carrier protein
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.107.016162

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 ( 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 = 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.