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Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases
Anssi J H Mykkänen1,2,3, Päivi Hirvensalo1,3,4, Kathrin Klein5,6
1Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Clinical Pharmacology and Therapeutics
|July 2, 2026
Summary
A novel CYP2C8*19 genetic variant impacts repaglinide pharmacokinetics and the drug interaction with gemfibrozil. This finding is crucial for understanding individual drug responses and optimizing treatment strategies.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Genetic Epidemiology
Background:
- CYP2C8 is a key enzyme in drug metabolism, influencing the pharmacokinetics of various medications.
- Understanding genetic variations in CYP2C8 is essential for predicting drug response and potential interactions.
- Repaglinide and gemfibrozil are index drugs metabolized by CYP2C8, making them valuable tools for studying enzyme activity.
Purpose of the Study:
- To identify and characterize novel genetic determinants of CYP2C8 activity.
- To investigate the impact of genetic variations on the pharmacokinetics of repaglinide and gemfibrozil.
- To elucidate the role of CYP2C8 and other genetic factors in the interaction between repaglinide and gemfibrozil.
Main Methods:
- Sequencing analysis to identify novel CYP2C8 alleles, including functional prediction.
- In vitro studies using human liver samples to assess the impact of genetic variants on CYP2C8 expression and activity.
- Pharmacokinetic studies in participants genotyped for CYP2C8 variants, measuring repaglinide and gemfibrozil concentrations.
- Genome-wide association studies (GWAS) to identify genetic loci associated with repaglinide pharmacokinetics, with and without gemfibrozil pretreatment.
Main Results:
- A novel functional CYP2C8 allele, CYP2C8*19, was identified, associated with reduced CYP2C8 mRNA and protein expression, and decreased enzyme activity.
- CYP2C8*19/*19 genotype was linked to significantly increased repaglinide exposure (AUC0-∞).
- Other CYP2C8 genotypes (CYP2C8*1/*3, CYP2C8*1/*4) also showed significant associations with altered repaglinide pharmacokinetics.
- The interaction between gemfibrozil and repaglinide was attenuated in individuals with the CYP2C8*19/*19 genotype.
- GWAS identified significant associations of SLCO1B1, SLCO1A2, and SLCO1C1 variants with repaglinide pharmacokinetics, particularly in the context of gemfibrozil interaction.
Conclusions:
- CYP2C8*19 is a novel decreased function allele that significantly affects repaglinide pharmacokinetics and the gemfibrozil-repaglinide interaction.
- Genetic variations in CYP2C8 and SLCO1B1 play a crucial role in modulating the pharmacokinetic interaction between gemfibrozil and repaglinide.
- These findings highlight the importance of pharmacogenomic profiling for personalized medicine, especially for drugs metabolized by CYP2C8.
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