Cytochrome P450 and Anticancer Drugs

Cytochrome P450 (CYP) is involved in the metabolism of a variety of anticancer drugs. CYP activities are known to be modified by several factors including genetic polymorphisms, changes in physiological conditions such as age, disease status or intake of certain drugs or foods or environmental factors such as smoking. These factors may cause interindividual differences in the pharmacokinetic profiles of anticancer drugs, leading to the variations of efficacy or toxicity of the drugs. Genetic polymorphisms present in CYPs sometimes result in the reduced activity of the enzymes causing low metabolic clearance of drugs or low production of active metabolites. For example, the formation of endoxifen, which is an active metabolite of tamoxifen, was less in patients with inactive polymorphic CYP2D6 than those with the wild type enzyme. CYP3A is the most abundant CYP expressed in the human liver and the small intestine that is involved in the metabolism of various anticancer drugs. The catalytic activity of CYP3A shows a large interindividual variability giving rise to large interindividual differences in the pharmacokinetic profiles of some anticancer drugs. So far, many attempts have been made to monitor the phenotypic activity of CYP3A in order to reduce the pharmacokinetic variations of anticancer drugs. Erythromycin, midazolam and cortisol are commonly used to monitor in vivo hepatic CYP3A activity. These methods have been applied to reduce the pharmacokinetic variations of docetaxel. Drug-drug interactions related to CYPs also modulate the pharmacokinetic profiles of anticancer drugs. These factors should be considered when trying to optimize and individualize chemotherapy.