Ward Family Heart Center, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO, USA.
Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, MO, USA.
J Clin Pharmacol. 2018 Jun;58(6):823-833. doi: 10.1002/jcph.1080. Epub 2018 Feb 22.
This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3- and 2.5-fold greater in 521CC and TC genotypes relative to 521TT (C , 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL; P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL; P < .0001). The impact of the SLCO1B1 c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1-mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.
本研究探讨了 SLCO1B1 等位基因变异对儿童和青少年辛伐他汀和辛伐他汀酸（SVA）系统暴露的影响。该基因编码肝脏特异性溶质载体有机阴离子转运蛋白家族成员 1B1 蛋白（SLCO1B1）。参与者（8-20 岁）至少有 1 个变异 SLCO1B1 c.521T>C 等位基因（521TC，n=15；521CC，n=2）和 2 个野生型等位基因（521TT，n=15）完成了单次口服剂量药代动力学研究。在等效剂量下，521CC 和 TC 基因型的 SVA 暴露量分别比 521TT 基因型高 6.3 倍和 2.5 倍（C ，2.1±0.2 比 1.0±0.5 比 0.4±0.3ng/mL；P<.0001；AUC，12.1±0.3 比 4.5±2.5 比 1.9±1.8ng·h/mL；P<.0001）。尽管在各基因型组内观察到 SVA 暴露的个体间差异很大，但 SLCO1B1 c.521 基因型的影响在儿童中更为明显。此外，25%的儿科参与者的 SVA 系统暴露可以忽略不计。需要进一步研究 SVA 形成和 SLCO1B1 介导的肝摄取的个体发育和遗传变异，以更好地了解儿童 SVA 暴露的变异性及其临床后果。
