The impact of CYP2C19 genotype on phenoconversion by concomitant medication

Area of Science:

• Pharmacogenetics
• Drug Metabolism
• Clinical Pharmacology

Background:

• Pharmacogenetics-guided prescribing adjusts drug dosage based on genetic profiles.
• Drug-drug interactions (DDIs) can cause phenoconversion, leading to discrepancies between predicted and observed drug metabolic phenotypes.
• CYP2C19 is a key enzyme involved in the metabolism of numerous drugs.

Purpose of the Study:

• To investigate the impact of CYP2C19 genotype on CYP2C19-dependent DDIs.
• To assess the concordance between genotype-predicted and observed CYP2C19 phenotypes.
• To evaluate the influence of DDIs on CYP2C19 activity across different genotypes.

Main Methods:

• Genotyping of CYP2C19 variants (*2, *3, *17) in 40 human liver samples.
• Assessing CYP2C19 activity using S-mephenytoin metabolism in microsomal fractions.
• Simulating DDIs by co-exposing microsomes to CYP2C19 inhibitors (fluvoxamine, voriconazole, omeprazole, pantoprazole).

Main Results:

• A 40% concordance was observed between predicted and measured CYP2C19 phenotypes, indicating significant phenoconversion.
• CYP2C19 activity was substantially inhibited by fluvoxamine, voriconazole, and omeprazole, but not pantoprazole.
• The impact of DDIs on CYP2C19 activity varied by genotype, with certain genotypes being more susceptible to phenoconversion.

Conclusions:

• Differential outcomes of CYP2C19-mediated DDIs across genotypes are mainly determined by basal CYP2C19 activity.
• CYP2C19 genotype can partially predict these outcomes, but disease-related factors like diabetes and liver disease also contribute to phenoconversion.
• Understanding phenoconversion is crucial for accurate pharmacogenetic interpretation and optimizing drug therapy.