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IN SILICO PREDICTION OF DRUG BINDING TO CYP2D6: IDENTIFICATION OF A NEW METABOLITE OF METOCLOPRAMIDE

Division of Cancer Medicine (J.Y., C.J.W., S.B., E.M.R.) and Molecular Pharmacology Unit (M.J.I.P., C.R.W.), Biomedical Research Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee, United Kingdom; Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science, University of Manchester, the Mill, Manchester, United Kingdom (J.-D.M., M.J.S.); and Department of Biochemistry, University of Leicester, Leicester, United Kingdom (C.A.K., G.C.K.R.)

Patients with cancer often take many different classes of drugs to treat the effects of their malignancy and the side effects of treatment, as well as their comorbidities. The potential for drug-drug interactions that may affect the efficacy of anticancer treatment is high, and a major source of such interactions is competition for the drug-metabolizing enzymes, cytochromes P450 (P450s). We have examined a series of 20 drugs commonly prescribed to cancer patients to look for potential interactions via CYP2D6. We used a homology model of CYP2D6, together with molecular docking techniques, to perform an in silico screen for binding to CYP2D6. Experimental IC₅₀ values were determined for these compounds and compared with the model predictions to reveal a correlation with a regression coefficient of r² = 0.61. Importantly, the docked conformation of the commonly prescribed antiemetic metoclopramide predicted a new site of metabolism that was further investigated through in vitro analysis with recombinant CYP2D6. An aromatic N-hydroxy metabolite of metoclopramide, consistent with predictions from our modeling studies, was identified by high-performance liquid chromatography/mass spectrometry. This metabolite was found to represent a major product of metabolism in human liver microsomes, and CYP2D6 was identified as the main P450 isoform responsible for catalyzing its formation. In view of the prevalence of interindividual variation in the CYP2D6 genotype and phenotype, we suggest that those experiencing adverse reactions with metoclopramide, e.g., extrapyramidal syndrome, are likely to have a particular CYP2D6 genotype/phenotype. This warrants further investigation.