Can the CEIBA Cocktail Designed for Human Cytochrome P450 Enzymes be Used in the Rat for Drug Interaction Studies?

Abstract

Purpose - The CEIBA cocktail consisting of caffeine (CAF), omeprazole (OZ), dextromethorphan (DM) and losartan (LOS) was previously proposed for the clinical phenotyping of five major human cytochrome P450 (CYP) isoenzymes. This work aimed to assess the usefulness of CEIBA cocktail to study non-clinical drug interactions in the rat. Methods - Wistar rats were divided into five groups to receive a single-oral dose of each probe drug (CAF, OZ, LOS, DM), individually or in combination as a cocktail. Plasma concentrations of the probe drugs and their metabolites [paraxanthine (1,7-X), 5-hydroxyomeprazole (5-OZ), losartan carboxylic acid (E-3174), dextrorphan (DX) and 3-methoxymorphinan (3-MM)] were determined by LC-MS/MS, and the corresponding pharmacokinetic parameters were estimated by non-compartmental analysis. The AUC_0-t and C_max drug/metabolite ratios (phenotypic metrics) were calculated for each probe drug and compared (probe alone versus cocktail). Results - The primary analysis of the pharmacokinetic data suggested the occurrence of pharmacokinetic-based drug interactions when the probe drugs were concurrently administered; such interactions were documented for CAF, 1,7-X, DX and E-3174. Nevertheless, except for the LOS/E-3174 probe drug-metabolite pair (p<0.05), there was little evidence that the probe drugs interacted metabolically as the metabolic ratios calculated were similar in both approaches. Moreover, no evidence was found for relevant pharmacodynamic interactions. Conclusion - CEIBA cocktail seems to be a useful tool to investigate drug interactions involving CYP isoenzymes in the rat, particularly at the level of CYP1A2, CYP2D1/2 and CYP2D2 isoforms using the CAF/1,7-X, OZ/5-OZ and DM/DX metabolic ratios, respectively.

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