title: Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters.
abstract: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.
authors.affiliation: a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.affiliation: a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.affiliation: a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.affiliation: a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D065727:Cytochrome P-450 CYP2C8 / Q000187:drug effects; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D015248:Gemfibrozil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000187:drug effects*
chemical_list: D065687:Cytochrome P-450 CYP2C8 Inhibitors; D005965:Glucuronates; D000960:Hypolipidemic Agents; D026901:Membrane Transport Proteins; C094370:gemfibrozil 1-O-acylglucuronide; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil
keywords: CYP2C8; OAT3; OATP1B1; drug-drug interaction; gemfibrozil; mechanism-based inhibition