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.
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 microM) 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 microM) 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.
Pharmacokinetics, Dyamics, and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. amit.kalgutkar@pfizer.com
Amit S
AS
Kalgutkar
Bo
B
Feng
Hang T
HT
Nguyen
Kosea S
KS
Frederick
Scott D
SD
Campbell
Heather L
HL
Hatch
Yi-An
YA
Bi
Diana C
DC
Kazolias
Ralph E
RE
Davidson
Rouchelle J
RJ
Mireles
David B
DB
Duignan
Edna F
EF
Choo
Sabrina X
SX
Zhao
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011422:Propionates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011422:Propionates; D011725:Pyridines; C525670:2-(4-(((2-(benzo(1,3)dioxol-5-yloxy)-pyridine-3-carbonyl)-amino)-methyl)-3-fluoro-phenoxy)-propionic acid; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C423013:Abcc2 protein, rat; C450859:SLCO2B1 protein, human; C503597:Slco1a4 protein, rat