CYP2C9 Genotype vs. Metabolic Phenotype for Individual Drug Dosing—A Correlation Analysis Using Flurbiprofen as Probe Drug

Abstract

Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type), and 0.113 for CYP2C9*3 (19 % of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.

Clinical application of a new warfarin-dosing regimen based on the CYP2C9 and VKORC1 genotypes in atrial fibrillation patients

“…The wild-type allele CYP2C9 * 1 shows normal enzyme activity and a high allelic frequency. The two allelic variants CYP2C9 * 2 and * 3 have allelic frequencies of ~13 and 7%, and lower enzyme activity in comparison to the wild-type (CYP2C9 * 1) (23). In the present study, the allelic variant CYP2C9 * 2 was not detected and is uncommon in the Han population.…”

Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine

“…The urine pH effect also impacts the interpretation of urinary concentration data. At present, the urinary concentrations of drugs and metabolites have been widely used for understanding drug pharmacokinetics, for phenotyping human subjects for certain metabolizing enzymes (Wedlund et al, 1984;Chládek et al, 2000;Vogl et al, 2015), and for testing and screening for illicit drug use (Fabbri, 2003;Moeller et al, 2017). As shown in Figures 5 and 6, the changes in urine pH will change the renal excretion and therefore urinary concentration-time profile.…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update

“…This change is based on data for multiple substrates (flurbiprofen, celecoxib, phenytoin, and warfarin) showing a similar effect of CYP2C9*1/*3 (AS = 1) and CYP2C9*2/*2 on metabolic ratio and dose requirements (warfarin). [9][10][11] Furthermore, CYP2C9*3 and alleles with a similar clinical effect and function are classified as "no function" alleles with a value of 0 for AS calculation. This is based on CYP2C9*3/*3, which represents the diplotype with the lowest metabolic activity and slowest pharmacokinetic clearance.…”