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

Abstract

Aims 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. Methods 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. Results 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. Conclusions 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.

A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances

“…18 Regarding the drug metabolic capacity score for exploring the overall effect of CYP2D6 and CYP2C19 on suicide severity, we propose a new system (Table 2, Figure 1) on the basis of two other previously suggested studies, evaluating their effect on different outcomes. 27,28 It is highlighted that the previous studies did not determine the presence of CYP2D6 duplications 27 or CYP2C19*17, 28 which are of relevance for the present work. Finally, once calculated the sum of the CYP2D6-CYPC19 allele activity scores, individuals were classified intro three groups characterized by having a: 'high' metabolic capacity corresponding to a drug metabolic capacity score above 4, 'medium' corresponding to a score equal to 4 or 'low' corresponding to a score lower than 4.…”

Length of Psychiatric Hospitalization is Correlated With CYP2D6 Functional Status in Inpatients with Major Depressive Disorder

“…The Tag-It™ Mutation Detection assays (Luminex Corporation, TX, USA) were utilized for the genotyping of 18 alleles of the CYP2D6 gene that were different from the reference functional allele *1 , as previously described for this cohort [37]. These assays employed PCR in order to selectively amplify the desired gene without coamplifying pseudogenes or other closely related sequences.…”

“…These drug metabolism indices were developed previously for multigene CYP450 combinatorial genotyping, and are modified here for a single gene, CYP2D6 [37,39]. Quantitative measures explaining CYP2D6 liver enzyme capacity and deviations from population averages simplify statistical procedures.…”

Physiogenomic Analysis of CYP450 Drug Metabolism Correlates Dyslipidemia With Pharmacogenetic Functional Status in Psychiatric Patients

“…Analysis in this study was done using the CYP450 combinatory and drug-specific metabolism indices described in our methodologies paper [38]. In summary, there are four combinatory indices: the drug metabolism reserve (metabolic reserve) index, the drug metabolism alteration (metabolic alteration) index, the allele alteration index and the gene alteration index.…”

“…Physiogenomic methods were used to quantify the genotypes according to the CYP450 combinatory and drug-specific metabolism indices described previously, namely the drug metabolism reserve index (metabolic reserve), drug metabolism alteration index (metabolic alteration), allele alteration index and gene alteration index [37,38]. This multigene physiogenomic analysis revealed significant correlations between all four indices and elevated LDLc, HDLc and LDLc:HDLc ratio.…”