How and Why to Screen for CYP2D6 Interindividual Variability in Patients Under Pharmacological Treatments

Abstract

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.

The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers

“…Approximately 25% of commonly prescribed and clinically important drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, opioids, anti-arrhythmics, antipsychotics, and some beta-blockers, are known to be CYP2D6 substrates [11][12][13][14]. However, CYP2D6 is characterized by a wide range of inter-individual and interethnic differences in activity (resulting in poor, intermediate, extensive and ultrarapid metabolizers), which is partly accounted for by extensive genetic polymorphism [12,15].…”

Primaquine Failure and Cytochrome P-450 2D6 in Plasmodium vivax Malaria

“…The institutional review boards of the Walter Reed Army Institute of Research, the Naval Medical Research Center, and the Walter Reed Army Medical Center, as well as the Western Institutional Review Board approved the study, and all participants provided written informed consent. CYP2D6 phenotyping was performed; 21 participants had an extensive-correspondence metabolizer phenotype (at least one allele coding for an enzyme with normal activity) (84%), 3 participants had an intermediate-metabolizer phenotype (heterozygous for one null and one reducedfunction allele) (12%), and 1 participant had a poor-metabolizer phenotype (two nonfunctional alleles) (4%) 4,5 (Table 1 in the Supplementary Appendix).…”

Pharmacogenetics at 50: Genomic Personalization Comes of Age

“…For example, the enzyme encoded by CYP2D6 exhibits a large degree of functional polymorphism, with some individuals carrying null (loss-of-function) alleles of the gene or lacking the gene entirely and others carrying over a dozen copies, with correspondingly wide variation in CYP2D6 activity (46,47). CYP2D6 also contributes to the metabolism of about half of all drugs on the market (48). Unsurprisingly then, CYP2D6 variation has been associated with the clinical pharmacokinetics of dozens of drugs (48), and references to CYP2D6 genetic variants as biomarkers have been included by the FDA on as many as 42 dif erent drug labels (www.fda.gov/Drugs/ ScienceResearch/ResearchAreas/Pharmacogenetics).…”