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 AUC0-t and Cmax 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. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Pharmacogenetics and therapeutic drug monitoring of fluoxetine in a real-world setting: A PK/PD analysis of the influence of (non-)genetic factors.

“…Thus, the future challenge that arises for the pharmacogenetics, including at the level of the CYP isoenzymes, is the redefinition of the classic system of phenotype classification, to translate and incorporate genetic and non-genetic-induced phenoconversion interactions into a real phenotype. Our purposed model for the assessment of the potential of drug-induced phenoconversion (DPI) opens the door for this new paradigm along with the phenotyping tests (Magalhães et al, 2016).…”

“…Phenoconversion is normally played by nongenetic factors, which change the genotype-phenotype relationship and, therefore, the genotype-drug clinical outcomes associations. Thus, the prediction of phenotype from genotype (i.e., gPH) is inaccurate, as well as the study of the variability of drug outcomes only based on genotype and genetic factors (de Leon, 2015; Magalhães, De Andrés, Falcão, Llerena, & Alves, 2016; Shah et al, 2016; Shah & Smith, 2015).…”

Evaluation of Cinnamon (Cinnamomum Verum) Effects on Liver CYP450 2D1 Activity and Hepatic Clearance in Diabetic Rats

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No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P‐glycoprotein

“…Cocktail approaches for phenotyping involving the administration of multiple CYP‐specific or P‐gp‐specific probe drugs were used to simultaneously assess the activities of these enzymes and the transporter P‐gp. Many phenotyping cocktails have been developed and used in recent years . For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail), which also included a probe drug for P‐gp (fexofenadine).…”

“…Many phenotyping cocktails have been developed and used in recent years. [20][21][22][23][24][25] For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail 26,27 ), which also included a probe drug for P-gp (fexofenadine). To our knowledge, this is the first seven-probe drug cocktail interaction study investigating St. John's wort.…”