Tipnoppanon Sayanit, Udomnilobol Udomsak, Siwamogsatham Sarawut, Vorasettakarnkij Yongkasem, Sukasem Chonlaphat, Prueksaritanont Thomayant, Chariyavilaskul Pajaree, Yodsurang Varalee, Srimatimanon Thanate, Chamnanphon Monpat, Vanwong Natchaya
The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Chulalongkorn University Drug Discovery and Drug Development Research Center (Chula4DR), Chulalongkorn University, Bangkok, Thailand.
Clin Transl Sci. 2025 May;18(5):e70225. doi: 10.1111/cts.70225.
Simvastatin, an HMG-CoA reductase inhibitor, is widely used for hypercholesterolemia but may cause myotoxicity linked to its plasma concentration. Pharmacokinetic gene polymorphisms influence inter-individual variability in simvastatin exposure. This study investigated the effects of pharmacokinetic gene polymorphisms on steady-state simvastatin plasma levels in Thai patients. Eighty-nine Thai patients with dyslipidemia or coronary artery disease on simvastatin treatment for at least 2 weeks without dose adjustment were recruited from King Chulalongkorn Memorial Hospital. Simvastatin lactone and acid concentrations were measured 12 h post-dose using UHPLC-MS/MS. Pharmacokinetic gene polymorphisms, including ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4, and CYP3A5, were genotyped by MassARRAY System. The results showed that patients with the SLCO1B1 c.521TC+CC genotype had significantly higher simvastatin acid levels than those with c.521TT (0.53 vs. 0.19 ng/mL, p = 0.03). Similarly, the SLCO1B1*1b/15 genotype was associated with higher simvastatin acid levels than SLCO1B11a/1a (0.58 vs. 0.16 ng/mL, p < 0.001). These findings suggest that SLCO1B1 c.521T>C, alone or with c.388A>G (SLCO1B11b/*15), reduces OATP1B1 function, leading to elevated simvastatin acid levels and increased myotoxicity risk. This study confirms the association of SLCO1B1 rs4149056 (c.521T>C) with higher simvastatin plasma levels in Thai patients. The study highlights the potential role of SLCO1B1 genotyping, particularly rs4149056 (c.521T>C) and rs2306283 (c.388A>G), in guiding statin therapy for Thai patients, which could help optimize treatment and reduce adverse effects such as statin-induced myotoxicity.
辛伐他汀是一种HMG-CoA还原酶抑制剂，广泛用于治疗高胆固醇血症，但可能因其血浆浓度而导致肌毒性。药代动力学基因多态性影响辛伐他汀暴露的个体间差异。本研究调查了药代动力学基因多态性对泰国患者辛伐他汀稳态血浆水平的影响。从朱拉隆功国王纪念医院招募了89名患有血脂异常或冠状动脉疾病且接受辛伐他汀治疗至少2周且未调整剂量的泰国患者。使用超高效液相色谱-串联质谱法在给药后12小时测量辛伐他汀内酯和酸的浓度。通过MassARRAY系统对包括ABCB1、ABCC2、ABCG2、SLCO1B1、SLCO1B3、CYP3A4和CYP3A5在内的药代动力学基因多态性进行基因分型。结果显示，携带SLCO1B1 c.521TC+CC基因型的患者辛伐他汀酸水平显著高于携带c.521TT基因型的患者（0.53对0.19 ng/mL，p = 0.03）。同样，SLCO1B1*1b/15基因型与高于SLCO1B11a/1a基因型的辛伐他汀酸水平相关（0.58对0.16 ng/mL，p < 0.001）。这些发现表明，SLCO1B1 c.521T>C单独或与c.388A>G（SLCO1B11b/*15）一起会降低OATP1B1功能，导致辛伐他汀酸水平升高和肌毒性风险增加。本研究证实了SLCO1B1 rs4149056（c.521T>C）与泰国患者较高的辛伐他汀血浆水平之间的关联。该研究强调了SLCO1B1基因分型，特别是rs4149056（c.521T>C）和rs2306283（c.388A>G）在指导泰国患者他汀类药物治疗中的潜在作用，这有助于优化治疗并减少诸如他汀类药物诱导的肌毒性等不良反应。
