Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-β-Glucuronide
Gemfibrozil
Repaglinide
Cerivastatin
Pioglitazone
Rosiglitazone
Active metabolite
CYP2C8
Glucuronide
Sulfapyridine
DOI:
10.1124/dmd.115.064303
Publication Date:
2015-05-05T01:31:38Z
AUTHORS (5)
ABSTRACT
Gemfibrozil has been suggested as a sensitive cytochrome P450 2C8 (CYP2C8) inhibitor for clinical investigation by the U.S. Food and Drug Administration European Medicines Agency. However, gemfibrozil drug-drug interactions (DDIs) are complex; its major circulating metabolite, 1-O-β-glucuronide (Gem-Glu), exhibits time-dependent inhibition of CYP2C8, both parent metabolite also behave moderate inhibitors organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. Additionally, inhibit renal transport mediated OAT3. Here, vitro data Gem-Glu were used to assess their impact on pharmacokinetics several victim drugs (including rosiglitazone, pioglitazone, cerivastatin, repaglinide) employing static mechanistic dynamic physiologically based pharmacokinetic (PBPK) models. Of 48 cases evaluated using models, about 75% 98% DDIs predicted within 1.5- 2-fold observed values, respectively, when incorporating interaction potential 1-O-β-glucuronide. Moreover, PBPK model was able recover plasma profiles repaglinide under control treatment conditions. Analyses suggest that is contributor DDIs, exposure needed bring complete inactivation CYP2C8 only fraction achieved clinic after therapeutic dose. Overall, complex can be quantitatively rationalized, learnings from this analysis applied support future predictions DDIs.
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