title: Hepatic Disposition of Gemfibrozil and Its Major Metabolite Gemfibrozil 1-O-β-Glucuronide.
abstract: Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems. Significant active uptake was noted in SCHH for the metabolite. GG, but not GEM, showed substrate affinity to organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1. In SCHH, glucuronidation was characterized affinity constants (Km) of 7.9 and 61.4 μM, and biliary excretion of GG was observed. Furthermore, GG showed active basolateral efflux from preloaded SCHH and ATP-dependent uptake into membrane vesicles overexpressing multidrug resistance-associated protein (MRP) 2, MRP3, and MRP4. A mathematical model was developed to estimate hepatic uptake and efflux kinetics of GEM and GG based on SCHH studies. Collectively, the hepatic transporters play a key role in the disposition and thus determine the local concentrations of GEM and more so for GG, which is the predominant inhibitory species against CYP2C8 and OATP1B1.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.affiliation: Systems Modeling and Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development , Cambridge, Massachusetts, 02139, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Scialis
authors.affiliation: Departments of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development , , Princeton, New Jersey 08540, United States.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Manthena V S
authors.initials: MV
authors.lastname: Varma
mesh_terms: D001692:Biological Transport; D002853:Chromatography, Liquid; D015248:Gemfibrozil / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008962:Models, Theoretical; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D015248:Gemfibrozil; D020719:Glucuronides; D000960:Hypolipidemic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C000715087:ABCC2 protein, human
keywords: gemfibrozil; gemfibrozil 1-O-β-glucuronide; hepatic disposition; mathematical modeling; multidrug resistance-associated proteins (MRPs); organic anion transporting polypeptide (OATP); sandwich-cultured human hepatocytes (SCHH); sinusoidal efflux