(-)-N-3-Benzylphenobarbital is superior to omeprazole and (+)-N-3-benzylnirvanol as a CYP2C19 inhibitor in suspended human hepatocytes

Marie-Lynn Cuypers, Hugues Chanteux, Eric Gillent, Pierre Bonnaillie, Kenneth Saunders, Claire Beckers, Claude Delatour, Sylvie Dell'Aiera, Anna-Lena Ungell, Johan Nicolaï
Drug Metabolism and Disposition: the Biological Fate of Chemicals 2020 August 24
Early assessment of metabolism pathways of new chemical entities (NCEs) guides the understanding of drug-drug interactions (DDIs). Selective enzyme inhibitors are indispensable in cytochrome P450 (CYP) reaction phenotyping. The most commonly applied CYP2C19 inhibitor, omeprazole, lacks selectivity. Two promising alternatives, (+)-N-3-benzylnirvanol and (-)-N-3-benzylphenobarbital, are already used as CYP2C19 inhibitors in some in vitro studies with suspended human hepatocytes. However, a full validation proving their suitability in terms of CYP and non-CYP selectivity has not been presented in literature. The present study provides a thorough comparison between omeprazole, (+)-N-3-benzylnirvanol, and (-)-N-3-benzylphenobarbital in terms of potency and selectivity, and shows the superiority of (-)-N-3-benzylphenobarbital as a CYP2C19 inhibitor in suspended human hepatocytes. Furthermore, we evaluated the application of (-)-N-3-benzylphenobarbital to predict the in vivo contribution of CYP2C19 to drug metabolism (fmCYP2C19 ). A set of ten clinically used CYP2C19 substrates with reported in vivo fmCYP2C19 data was evaluated. FmCYP2C19 , which was predicted using data from suspended human hepatocyte incubations, underestimated the in vivo fmCYP2C19 The use of a different hepatocyte batch with a different CYP3A4/CYP2C19 activity ratio, showed the impact of intrinsic CYP activities on the determination of fmCYP2C19 Overall, this study confirms the selective CYP2C19 inhibition by (-)-N-3-benzylphenobarbital over other CYP isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4) and clinically relevant non-CYP enzymes (AO, FMO3, NAT2, UGT1A1, UGT1A4, UGT2B7, UGT2B15) in suspended human hepatocytes. (-)-N-3-benzylphenobarbital is therefore the preferred CYP2C19 inhibitor to assess fmCYP2C19 in suspended human hepatocytes in comparison to omeprazole and (+)-N-3-benzylnirvanol. Significance Statement (-)-N-3-benzylphenobarbital is a more potent and selective inhibitor of CYP2C19 in suspended human hepatocytes than omeprazole. (-)-N-3-benzylphenobarbital can be used to predict the fraction metabolized by CYP2C19 in suspended human hepatocytes.

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