Khwarg Juyoung, Yang Eunsol, Park Chan Song, Ji Sang Chun, Yu Kyung-Sang, Lee SeungHwan
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Clin Transl Sci. 2024 Dec;17(12):e70103. doi: 10.1111/cts.70103.
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 1022C>T increased the systemic exposure of proguanil, while decreasing the systemic exposure of cycloguanil by reducing the hepatic uptake of proguanil, as mechanistically described by a population PK approach.
氯胍是一种抗疟药物，通过多态性有机阳离子转运体1（OCT1）进行肝脏摄取，随后被细胞色素P-450 2C19（CYP2C19）酶代谢为其活性代谢产物环氯胍。本研究旨在评估编码OCT1的SLC22A1基因多态性对氯胍和环氯胍在韩国人群中药代动力学（PK）的影响，并从机制上进行表征。本研究基于一项CYP2C19介导的药物相互作用研究（NCT04568772）的PK结果进行事后分析。在先前研究纳入的16名CYP2C19正常代谢者中，对13名与OCT1功能降低相关的6个SLC22A1单核苷酸多态性（SNP）进行了前瞻性基因分型。其中，仅观察到SNP SLC22A1 1022C>T（rs2282143），4名受试者为杂合子（CT），9名受试者为野生型等位基因纯合子（CC）。与CC基因型受试者相比，CT基因型显示氯胍的全身暴露高1.2倍，环氯胍的暴露低0.6倍，导致代谢比低0.5至0.6倍。基于PK和基因型数据，采用非线性混合效应建模方法建立了一个包括充分搅拌肝脏隔室的母体-代谢物联合群体PK模型。估计CT基因型的OCT1活性比CC基因型低0.42倍。总之，如群体PK方法从机制上所描述的，SLC22A1 1022C>T基因多态性增加了氯胍的全身暴露，同时通过减少氯胍的肝脏摄取降低了环氯胍的全身暴露。
