Role of Cytochrome P450 Activity in the Fate of Anticancer Agents and in Drug Resistance
- 1 January 2005
- journal article
- review article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 44 (4), 349-366
- https://doi.org/10.2165/00003088-200544040-00002
Abstract
Although activity of cytochrome P450 isoenzymes (CYPs) plays a major role in the fate of anticancer agents in patients, there are relatively few clinical studies that evaluate drug metabolism with therapeutic outcome. Nevertheless, many clinical reports in various non-oncology fields have shown the dramatic importance of CYP activity in therapeutic efficacy, safety and interindividual variability of drug pharmacokinetics. Moreover, variability of drug metabolism in the liver as well as in cancer cells must also be considered as a potential factor mediating cancer resistance. This review underlines the role of drug metabolism mediated by CYPs in pharmacokinetic variability, drug resistance and safety. As examples, biotransformation pathways of tamoxifen, paclitaxel and imatinib are reviewed. This review emphasises the key role of therapeutic drug monitoring as a complementary tool of investigation to in vitro data. For instance, pharmacokinetic data of anticancer agents have not often been published within subpopulations of patients who show ultra-rapid, extensive or poor metabolism (e.g. due to CYP2D6 and CYP2C19 genotypes). Besides kinetic variability in the systemic circulation, induction of CYP activity may participate in creating drug resistance by speeding up the cancer agent degradation specifically in the target cells. For one cancer agent, various mechanisms of resistance are usually identified within different cell clones. This review also tries to emphasise that drug resistance mediated by CYP activity in cancer cells should be taken into consideration to a greater degree. The unequivocal identification of the metabolising enzymes involved in clinical conditions will eventually allow improvement and individualisation of anticancer agent therapy, i.e. drug dosage and selection. In addition, a more complete understanding of the metabolism of anticancer agents will assist in the prediction of drug-drug interactions, as anticancer agent combinations are becoming more prevalent.Keywords
This publication has 167 references indexed in Scilit:
- The Erythromycin Breath Test For the Prediction of Drug ClearanceClinical Pharmacokinetics, 2001
- PharmacogeneticsClinical Pharmacokinetics, 2000
- Clinically relevant drug–drug interactions in oncologyBritish Journal of Clinical Pharmacology, 1998
- Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.JCI Insight, 1997
- Metabolic activation of toxins: tissue-specific expression and metabolism in target organs.Environmental Health Perspectives, 1997
- Effects of dietary broccoli on human drug metabolising activityCancer Letters, 1997
- Use of Probe Drugs as Predictors of Drug Metabolism in HumansThe Journal of Clinical Pharmacology, 1997
- Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the Rhesus monkey: Does liver accumulation of inhibitory metabolities protect from tamoxifen-dependent genotoxicity and cancer?Carcinogenesis: Integrative Cancer Research, 1996
- The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.British Journal of Clinical Pharmacology, 1995
- Extrahepatic Metabolism of Drugs in HumansClinical Pharmacokinetics, 1994