title: Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate.
abstract: Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical step in the drug discovery process. Although in vitro studies with CYP3A4, CYP2C9, and CYP2C19 have suggested the presence of multiple binding regions within the P450 active site based on probe substrate-dependent inhibition profiles, similar studies have not been performed with CYP2C8. The ability to understand CYP2C8 probe substrate sensitivity will enable appropriate in vitro and in vivo probe selection. To characterize the potential for probe substrate-dependent inhibition with CYP2C8, the inhibition potency of 22 known inhibitors of CYP2C8 were measured in vitro using four clinically relevant CYP2C8 probe substrates (montelukast, paclitaxel, repaglinide, and rosiglitazone) and amodiaquine. Repaglinide exhibited the highest sensitivity to inhibition in vitro. In vitro phenotyping indicated that montelukast is an appropriate probe for CYP2C8 inhibition studies. The in vivo sensitivities of the CYP2C8 probe substrates cerivastatin, fluvastatin, montelukast, pioglitazone, and rosiglitazone were determined in relation to repaglinide on the basis of clinical drug-drug interaction (DDI) data. Repaglinide exhibited the highest sensitivity in vivo, followed by cerivastatin, montelukast, and pioglitazone. Finally, the magnitude of in vivo CYP2C8 DDI caused by gemfibrozil-1-O-β-glucuronide was predicted. Comparisons of the predictions with clinical data coupled with the potential liabilities of other CYP2C8 probes suggest that montelukast is an appropriate CYP2C8 probe substrate to use for the in vivo situation.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: VandenBrink
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.forename: Dan A
authors.initials: DA
authors.lastname: Rock
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: Jan L
authors.initials: JL
authors.lastname: Wahlstrom
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000655:Amodiaquine / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002219:Carbamates / Q000494:pharmacology; D003521:Cyclopropanes; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D000077154:Rosiglitazone; D012680:Sensitivity and Specificity; D013379:Substrate Specificity; D013440:Sulfides; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000085:Acetates; D002219:Carbamates; D003521:Cyclopropanes; D010880:Piperidines; D011804:Quinolines; D013440:Sulfides; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000655:Amodiaquine; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; C093875:montelukast; D017239:Paclitaxel