PT  - JOURNAL ARTICLE
AU  - Brooke M VandenBrink
AU  - Robert S Foti
AU  - Dan A Rock
AU  - Larry C Wienkers
AU  - Jan L Wahlstrom
TI  - Evaluation of CYP2C8 Inhibition In Vitro: Utility of Montelukast as a Selective CYP2C8 Probe Substrate
AID  - 10.1124/dmd.111.039065
DP  - 2011 Jun 22
TA  - Drug Metabolism and Disposition
PG  - dmd.111.039065
4099  - http://dmd.aspetjournals.org/content/early/2011/06/22/dmd.111.039065.short
4100  - http://dmd.aspetjournals.org/content/early/2011/06/22/dmd.111.039065.full
AB  - Understanding the potential for cytochrome P450 mediated drug-drug interactions is a critical step in the drug discovery process. While in vitro studies with CYP3A4, CYP2C9 and CYP2C19 have suggested the presence of multiple binding regions within the P450 active site based upon probe substrate-dependent inhibition profiles, similar studies have not been carried out with CYP2C8. In order to characterize the potential for probe substrate-dependent inhibition with CYP2C8, the inhibition potency of twenty-two 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 based upon clinical 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-glucoronide was predicted. Comparisons of the predictions with clinical data suggest that montelukast is an appropriate CYP2C8 probe substrate to use for the in vivo situation.