CYP450 Genotype—Phenotype Concordance Using the Geneva Micrococktail in a Clinical Setting

Abstract

Pharmacokinetic variability is a major source of differences in drug response and can be due to genetic variants and/or drug-drug interactions. Cytochromes P450 are among the most studied enzymes from a pharmacokinetic point of view. Their activity can be measured by phenotyping, and/or predicted by genotyping. Depending on the presence of drugs and/or diseases that can affect their in vivo activity, both approaches can be complementary. In 2014, the Geneva cocktail using dried blood spots was validated in healthy volunteers for CYP450 phenotyping. Since its clinical implementation, it has been used in approximately 500 patients in various clinical situations. Our study aims to report the concordance between CYP450 genotype and phenotype in real-life patients. The prospectively collected data from patients who were genotyped and/or phenotyped between January 2014 and December 2020 were reviewed. A total of 537 patients were genotyped and/or phenotyped for CYP450 during this period, and 241 underwent simultaneous genotyping and phenotyping allowing for genotype/phenotype concordance assessment. Genotyping correctly predicted poor metabolizer phenotypes for most CYPs isoenzymes studied, whereas agreement was more variable for intermediate, normal, and ultrarapid metabolizers. Discrepancies between the phenotype predicted on the basis of genotyping and the measured phenotype were not always explained by concurrent medication (phenotypic switch). Therefore genotyping and phenotyping tests are complementary approaches when aiming to individualize drug therapy. In the 537 patients, the majority of clinical situations were observed with analgesic/anesthetic drugs (n = 187), followed by antidepressants (n = 153), antineoplastics (n = 97), and immunosuppressants (n = 93). Inefficacy (or low drug levels) and adverse drug reaction (or high drug levels) were the main reasons for testing. Genotype and/or phenotype results explained or at least contributed to the clinical event in 44% of cases.

CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity

“…The present work investigated the association between CYP1A2 genetic polymorphisms and CYP1A2-selective phenacetin O-dealkylation activity or CYP1A2 mRNA expression in human liver tissues and in psychiatric patients belonging to Caucasian populations. A high inter-individual variability in the CYP1A2 activity and expression was observed in the liver tissue donors, which was consistent with the results obtained from human liver samples in a recent study by Liu et al [31] and with the CYP1A2 phenotype prediction in patients by Lorenzini et al [51]. The frequencies of the liver tissue donors with poor, intermediate and normal CYP1A2 activities were more or less similar to the frequency distribution of poor, normal and ultra-rapid metabolizer phenotypes in patients reported by Lorenzini et al [51].…”

“…A high inter-individual variability in the CYP1A2 activity and expression was observed in the liver tissue donors, which was consistent with the results obtained from human liver samples in a recent study by Liu et al [31] and with the CYP1A2 phenotype prediction in patients by Lorenzini et al [51]. The frequencies of the liver tissue donors with poor, intermediate and normal CYP1A2 activities were more or less similar to the frequency distribution of poor, normal and ultra-rapid metabolizer phenotypes in patients reported by Lorenzini et al [51]. In a previous study [52], a strong correlation was reported between hepatic CYP1A2 activity and mRNA expression, which was confirmed by our findings in the liver tissue donors.…”

“…The substantial variability in hepatic CYP1A2 function was attributed to both genetic polymorphisms and non-genetic factors [ 10 , 27 , 51 ]. Several CYP1A2 allelic variants have been associated with altered CYP1A2 activity and/or mRNA expression.…”

Practice of CYP450 genotyping and phenotyping in children in a real-life setting

“…This study is a paediatric subpart of three previously published studies that included children and adults (Lloret-Linares et al, 2017;Rollason et al, 2020a;Ing Lorenzini et al, 2021). The studies were approved by the Ethics Commission of the Canton of Geneva, Geneva (Switzerland) (study numbers: 15-225, 15-080 and 14-244) (Lloret-Linares et al, 2017;Rollason et al, 2020a;Ing Lorenzini et al, 2021).…”

CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function

“…The present work indicated that CYP2B6 genetic polymorphisms influenced the expression and activity of CYP2B6 enzyme to some extent; however, the significance of phenoconverting non-genetic factors in enzyme function was comparable with that of genetic factors or even phenoconversion masked the effect of CYP2B6 allelic variants. Ing Lorenzini et al evaluated the predictive values of CYP genotypes on CYP-mediated drug metabolism in patients, and observed relatively good CYP2B6 genotype–phenotype concordance for poor and rapid metabolizers (67% and 100%), but more variable for intermediate and normal metabolizers (0% and 38%) 89 . It should be noted that the number of patients involved in the interpretation of CYP2B6 genotype–phenotype concordance was limited (N = 36).…”