Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

Abstract

The majority of phase I-and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15-25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7.

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

“…The dosing required to achieve the same plasma levels of a drug mainly metabolized by CYP2D6 can differ 10-to 30-fold between individuals. 1 Thus, standard doses of drugs in PMs can either lead to exaggerated drug response or excessive side effects whereas the other extreme, that is UMs, may suffer from therapeutic failure as they show extremely high enzymatic activity resulting in lower drug concentrations. The function of the CYP2D6 polymorphisms in drug interaction profiles, side effects and therapeutic outcome is well documented for UMs and PMs.…”

“…Cytochrome P450 enzymes are responsible for 70-80% of all phase-I-dependent metabolism in approximately 40-45% of all marketed drugs. 1 Genetic polymorphisms have been shown to cause wide interindividual differences in the metabolic activity of CYP P450 enzymes, thus influencing pharmacokinetics, efficacy and adverse effects of pharmaceutical drug treatment. 2 Especially well characterized is the highly polymorphic cytochrome P450 2D6 (CYP2D6) isoenzyme for which over 80 alleles and over 150 variations have been described with widely varying frequencies between different ethnicities (cf Home Page of the Human Cytochrome P450 Allele Nomenclature Committee, http:// www.imm.ki.se/cypalleles).…”

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

“…All other factors being equal, human genetics can alter drug exposure. Understanding the role of genetic polymorphisms in genes encoding proteins and enzymes involved in drug absorption, distribution, metabolism, elimination, and action is important for better understanding the interindividual differences in drug pharmacokinetics and pharmacodynamics (9). Depending on the alleles carried by an individual, drug metabolism can be either enhanced, decreased, or abolished (10).…”

Cytochrome P450 pharmacogenetics and cancer

“…Based on the composition of the alleles, the affected individuals might be divided into four major phenotypes: poor metabolizers (PMs), having two nonfunctional genes, intermediate metabolizers (IMs) being deficient on one allele, extensive metabolizers (EMs) having two copies of normal genes and ultrarapid metabolizers (UMs) having three or more functional active gene copies (see Ingelman-Sundberg, 2004b;Ingelman-Sundberg and Rodriguez-Antona, 2005). In the CYP gene family, the most penetrant genetic alterations are gene deletions, missense mutations and mutations creating splicing defects and premature stop codons.…”