The majority of human P450-dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced metabolism. The latter situation is due to stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes. An updated list of variant CYP alleles is present at the Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/). Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. Dosage requirements for several commonly used drugs that have a narrow therapeutic range can differ more than 20-fold dependent on the genotype or the enzyme expression status.
Unfortunately, clinical use is in its infancy. Until simpler and more rapid tests become commercially available, phenotyping may remain largely a research tool, or one with applicability limited to special populations likely to have significantly abnormal activity, particularly those patients who are suspected to have liver disease, declining hepatic function, or who may be receiving inducers or inhibitors of CYP3A4.
E. D. Kharasch, K. E. Thummel, and P. B. Watkins
CYP3A Probes Can Quantitatively Predict the In Vivo Kinetics of Other CYP3A Substrates and Can Accurately Assess CYP3A Induction and Inhibition
Mol. Interv., June 1, 2005; 5(3): 151 – 153.
Noboru Yamamoto, Tomohide Tamura, Haruyasu Murakami, Tatsu Shimoyama, Hiroshi Nokihara, Yutaka Ueda, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Tetsuro Kodama, Mikiko Shimizu, Kazuto Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous CortisolRandomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol JCO 2005 23: 1061-1069