Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure

Abstract

This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration–time curve from time zero to infinity (AUC_0-∞) than participants with CYP2C8*1/*1 (P = 1.6 × 10⁻⁴). Participants with CYP2C8*1/*3 had 26% smaller AUC_0-∞ (P = 0.0033) and those with CYP2C8*1/*4 had 51% greater AUC_0-∞ (P = 8.2 × 10⁻⁴). The fold increase in repaglinide AUC_0-∞ caused by gemfibrozil was 36% (P = 1.3 × 10⁻⁴) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521 T>C (rs4149056) associated with increased repaglinide AUC_0-∞ (P = 4.5 × 10⁻¹⁵; n = 172) and SLCO1A2 variants associated with decreased AUC_0-∞ (P < 10⁻⁸). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC_0-∞ (P < 1.6 × 10⁻⁸; n = 66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC_0-∞ following gemfibrozil than participants with the normal function SLCO1B1 genotype (P = 0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil–repaglinide interaction.