Kivrane Agnija, Ulanova Viktorija, Grinberga Solveiga, Sevostjanovs Eduards, Viksna Anda, Ozere Iveta, Bogdanova Ineta, Zolovs Maksims, Ranka Renate
Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, LV1067 Riga, Latvia.
Pharmacogenetic and Precision Medicine Laboratory, Pharmaceutical Education and Research Centre, Riga Stradins University, Konsula Street 21, LV1007 Riga, Latvia.
Pharmaceutics. 2024 Mar 12;16(3):388. doi: 10.3390/pharmaceutics16030388.
Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR). However, the effect of genetic polymorphisms on the anti-tuberculosis (anti-TB) drug, and particularly rifampicin (RIF), exposure or anti-TB drug-induced liver injury (DILI) remains uncertain. Here, we evaluated the relationship between single nucleotide polymorphisms (SNPs) detected in the RIF pharmacogenes (, , , , and ) and RIF PK parameters, as well as anti-TB treatment-associated DILI. In total, the study enrolled 46 patients with drug-susceptible pulmonary TB. The RIF plasma concentration was measured using the LC-MS/MS method in the blood samples collected pre-dose and 2 and 6 h post-dose, whilst the DILI status was established using the results from blood biochemical analysis performed before and 10-12 days after treatment onset. The genotyping was conducted using a targeted NGS approach. After adjustment for confounders, the patients carrying the rs3732357 GA/AA genotype of the gene were found to have significantly lower RIF plasma AUC in comparison to those with GG genotype, while the difference in RIF plasma C was insignificant. None of the analyzed SNPs was related to DILI. Hence, we are the first to report intronic SNP rs3732357 as the genetic component of variability in RIF exposure. Regarding anti-TB treatment-associated DILI, the other preexisting factors promoting this ADR should be considered.
基因多态性可对药物药代动力学（PK）和药物不良反应（ADR）的发生产生相当大的影响。然而，基因多态性对抗结核药物，尤其是利福平（RIF）的暴露或抗结核药物引起的肝损伤（DILI）的影响仍不确定。在此，我们评估了在RIF药物代谢基因（ 、 、 、 和 ）中检测到的单核苷酸多态性（SNP）与RIF PK参数以及抗结核治疗相关DILI之间的关系。该研究共纳入了46例药物敏感型肺结核患者。在给药前以及给药后2小时和6小时采集的血样中，使用液相色谱-串联质谱法（LC-MS/MS）测定RIF血浆浓度，同时根据治疗开始前和治疗开始后10 - 12天进行的血液生化分析结果确定DILI状态。使用靶向二代测序（NGS）方法进行基因分型。在对混杂因素进行校正后，发现携带 基因rs3732357 GA/AA基因型的患者与携带GG基因型的患者相比，RIF血浆AUC显著更低，而RIF血浆Cmax的差异不显著。分析的SNP均与DILI无关。因此，我们首次报道内含子SNP rs3732357是RIF暴露变异性的遗传因素。关于抗结核治疗相关DILI，应考虑其他促进这种ADR发生的既往因素。
