Involvement of Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes in the in Vitro Metabolism of Muraglitazar
- 24 October 2006
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 35 (1), 139-149
- https://doi.org/10.1124/dmd.106.011932
Abstract
Muraglitazar (Pargluva), a dual α/γ peroxisome proliferator-activated receptor activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. The human major primary metabolic pathways of muraglitazar include acylglucuronidation, aliphatic/aryl hydroxylation, and O-demethylation. This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of muraglitazar. [14C]Muraglitazar was metabolized by cDNA-expressed CYP2C8, 2C9, 2C19, 2D6, and 3A4, but to a very minimal extent by CYP1A2, 2A6, 2B6, 2C18, 2E1, and 3A5. Inhibition of the in vitro metabolism of muraglitazar in human liver microsomes, at a clinically efficacious concentration, by chemical inhibitors and monoclonal antibodies further supported involvement of CYP2C8, 2C9, 2C19, 2D6, and 3A4 in its oxidation. A combination of intrinsic clearance (Vmax/Km) and relative concentrations of each P450 enzyme in the human liver was used to predict the contribution of CYP2C8, 2C9, 2C19, 2D6, and 3A4 to the formation of each primary oxidative metabolite and to the overall oxidative metabolism of muraglitazar. Glucuronidation of [14C]muraglitazar was catalyzed by cDNA-expressed UGT1A1, 1A3, and 1A9, but not by UGT1A6, 1A8, 1A10, 2B4, 2B7, and 2B15. The Km values for muraglitazar glucuronidation by the three active UGT enzymes were similar (2–4 μM). In summary, muraglitazar was metabolized by multiple P450 and UGT enzymes to form multiple metabolites. This characteristic predicts a low potential for the alteration of the pharmacokinetic parameters of muraglitazar via polymorphic drug metabolism enzymes responsible for clearance of the compound or by coadministration of drugs that inhibit or induce relevant metabolic enzymes.Keywords
This publication has 25 references indexed in Scilit:
- Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin MonotherapyDiabetes Care, 2006
- Monoclonal Antibodies and Multifunctional Cytochrome P450: Drug Metabolism as ParadigmThe Journal of Clinical Pharmacology, 2006
- Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db MiceDiabetes, 2006
- Design and Synthesis of N-[(4-Methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a Novel Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist with Efficacious Glucose and Lipid-Lowering ActivitiesJournal of Medicinal Chemistry, 2004
- THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVEDrug Metabolism and Disposition, 2003
- The Glucuronidation of Exogenous and Endogenous Compounds by Stably Expressed Rat and Human UDP-Glucuronosyltransferase 1.1Archives of Biochemistry and Biophysics, 1996
- P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclaturePharmacogenetics, 1996
- Interaction of Sulfaphenazole Derivatives with Human Liver Cytochromes P450 2C: Molecular Origin of the Specific Inhibitory Effects of Sulfaphenazole on CYP 2C9 and Consequences for the Substrate Binding Site Topology of CYP 2C9Biochemistry, 1996
- Drug glucuronidation in humansPharmacology & Therapeutics, 1991
- Pharmacokinetics and dose proportionality of ketoconazole in normal volunteersAntimicrobial Agents and Chemotherapy, 1986