In silico prediction of drug binding to CYP2D6: identification of a new metabolite of metoclopramide.
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.
Yu
Jinglei
J
Division of Cancer Medicine, Biomedical Research Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, UK.
Paine
Mark J I
MJ
Maréchal
Jean-Didier
JD
Kemp
Carol A
CA
Ward
Clive J
CJ
Brown
Simon
S
Sutcliffe
Michael J
MJ
Roberts
Gordon C K
GC
Rankin
Elaine M
EM
Wolf
C Roland
CR
D000932:Antiemetics / Q000378:metabolism; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008787:Metoclopramide / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism
D000932:Antiemetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6; D009251:NADPH-Ferrihemoprotein Reductase; D008787:Metoclopramide