Novel Drug Metabolism Indices for Pharmacogenetic Functional Status Based on Combinatory Genotyping of CYP2C9 , CYP2C19 and CYP2D6 Genes

• Published in: Biomarkers in medicine Vol. 5; no. 4; pp. 427 - 438
• Main Authors: Villagra, David, Goethe, John, Schwartz, Harold I, Szarek, Bonnie, Kocherla, Mohan, Gorowski, Krystyna, Windemuth, Andreas, Ruaño, Gualberto
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.08.2011
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antidepressants; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Child; Child, Preschool; Clinical trials; Cytochrome P-450; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Drug metabolism; Epigenetics; Female; Genes; Genetic aspects; Genetic Association Studies; Genetic Loci; Genotype; Genotype & phenotype; Human subjects; Humans; Male; Middle Aged; Pharmaceutical Preparations - metabolism; Physiological aspects; Polymorphism, Single Nucleotide; Ratings & rankings; United States
• ISSN: 1752-0363; 1752-0371; 1752-0371
• DOI: 10.2217/bmm.11.32

We aim to demonstrate clinical relevance and utility of four novel drug-metabolism indices derived from a combinatory (multigene) approach to CYP2C9, CYP2C19 and CYP2D6 allele scoring. Each index considers all three genes as complementary components of a liver enzyme drug metabolism system and uniquely benchmarks innate hepatic drug metabolism reserve or alteration through CYP450 combinatory genotype scores. A total of 1199 psychiatric referrals were genotyped for polymorphisms in the CYP2C9, CYP2C19 and CYP2D6 gene loci and were scored on each of the four indices. The data were used to create distributions and rankings of innate drug metabolism capacity to which individuals can be compared. Drug-specific indices are a combination of the drug metabolism indices with substrate-specific coefficients. The combinatory drug metabolism indices proved useful in positioning individuals relative to a population with regard to innate drug metabolism capacity prior to pharmacotherapy. Drug-specific indices generate pharmacogenetic guidance of immediate clinical relevance, and can be further modified to incorporate covariates in particular clinical cases. We believe that this combinatory approach represents an improvement over the current gene-by-gene reporting by providing greater scope while still allowing for the resolution of a single-gene index when needed. This method will result in novel clinical and research applications, facilitating the translation from pharmacogenomics to personalized medicine, particularly in psychiatry where many drugs are metabolized or activated by multiple CYP450 isoenzymes.