ABSTRACT:Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for phase I drug metabolism of many anticancer agents. It is also a major route for metabolism of many drugs used by patients to treat the symptoms caused by cancer and its treatment as well as their other illnesses, for example, cardiovascular disease. To assess the ability to inhibit CYP3A4 of drugs most commonly used by our patients during cancer therapy, we have made in silico predictions based on the crystal structures of CYP3A4. From this set of 33 common comedicated drugs, 10 were predicted to be inhibitors of CYP3A4, with the antidiarrheal drug loperamide predicted to be the most potent. Cytochrome P450 3A4 (CYP3A4) is the major xenobiotic metabolizing enzyme in humans. A broad specificity coupled with high levels of expression in the liver means it is responsible for the metabolism of more than half of all prescribed drugs (Guengerich, 1997). When patients receive several medications concurrently, unwanted and life-threatening effects can result from the competition for the same drug-metabolizing enzyme affecting the blood levels of the competing drugs. Cancer patients would seem to be significantly at risk in this respect, because CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e.g., analgesics) and side effects (e.g., antiemetics and antidiarrheals) and to treat comorbidities. The anticancer drugs metabolized by CYP3A4 include docetaxel (Marre et al

ABSTRACT: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 IC 50 values were determined for these compounds and compared with the model predictions to reveal a correlation with a regression coefficient of r 2 ‫؍‬ 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 highperformance 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.

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