Effect of SLC22A1 polymorphism on the pharmacokinetics of proguanil in Korean: A semi-physiologic population pharmacokinetic approach
Abstract
Proguanil, an antimalarial drug, undergoes hepatic uptake by the polymorphic organic cation transporter 1 (OCT1) and is subsequently metabolized by the cytochrome P-450 2C19 (CYP2C19) enzyme into its active metabolite, cycloguanil. This study aims to evaluate and mechanistically characterize the effect of genetic polymorphism of SLC22A1, which encodes OCT1, on the pharmacokinetics (PKs) of proguanil and cycloguanil in Korean. This study was based on a post hoc analysis of the PK results of a CYP2C19 mediated drug-drug interaction study (NCT04568772). Among the 16 CYP2C19 normal metabolizers enrolled in the previous study, 13 were prospectively genotyped for six SLC22A1 single nucleotide polymorphisms (SNPs) associated with a decreased function of OCT1. Among these, only the SNP SLC22A1 1022C>T (rs2282143) was observed, with four subjects being heterozygous (CT) and nine subjects homozygous for the wild-type allele (CC). The CT genotype showed a 1.2-fold higher systemic exposure of proguanil and a 0.6-fold lower exposure of cycloguanil compared to those in subjects with the CC genotype, resulting in a 0.5 to 0.6-fold lower metabolic ratio. Based on the PK and genotype data, a parent-metabolite joint population PK model including a well-stirred liver compartment was developed using a nonlinear mixed-effect modeling approach. The OCT1 activity of the CT genotype was estimated to be 0.42-fold lower compared to the CC genotype. In conclusion, the genetic polymorphism of SLC22A1…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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