Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Clin Transl Sci. 2024 Apr;17(4):e13795. doi: 10.1111/cts.13795.
N-acetyltransferase 2 (NAT2) genetic polymorphisms might alter isoniazid metabolism leading to toxicity. We reviewed the impact of NAT2 genotype status on the pharmacokinetics, efficacy, and safety of isoniazid, a treatment for tuberculosis (TB). A systematic search for research articles published in Scopus, PubMed, and Embase until August 31, 2023, was conducted without filters or limits on the following search terms and Boolean operators: "isoniazid" AND "NAT2." Studies were selected if NAT2 phenotypes with pharmacokinetics or efficacy or safety of isoniazid in patients with TB were reported. Patient characteristics, NAT2 status, isoniazid pharmacokinetic parameters, early treatment failure, and the prevalence of drug-induced liver injury were extracted. If the data were given as a median, these values were standardized to the mean. Forty-one pharmacokinetics and 53 safety studies were included, but only one efficacy study was identified. The average maximum concentrations of isoniazid were expressed as supratherapeutic concentrations in adults (7.16 ± 4.85 μg/mL) and children (6.43 ± 3.87 μg/mL) in slow acetylators. The mean prevalence of drug-induced liver injury was 36.23 ± 19.84 in slow acetylators, which was significantly different from the intermediate (19.49 ± 18.20) and rapid (20.47 ± 20.68) acetylators. Subgroup analysis by continent showed that the highest mean drug-induced liver injury prevalence was in Asian slow acetylators (42.83 ± 27.61). The incidence of early treatment failure was decreased by genotype-guided isoniazid dosing in one study. Traditional weight-based dosing of isoniazid in most children and adults yielded therapeutic isoniazid levels (except for slow acetylators). Drug-induced liver injury was more commonly observed in slow acetylators. Genotype-guided dosing may prevent early treatment failure.
N-乙酰基转移酶 2（NAT2）基因多态性可能改变异烟肼的代谢，导致毒性。我们综述了 NAT2 基因型对异烟肼（治疗结核病的药物）药代动力学、疗效和安全性的影响。我们在 Scopus、PubMed 和 Embase 中进行了系统的文献检索，检索时间截至 2023 年 8 月 31 日，未对以下检索词和布尔运算符设置过滤器或限制：“isoniazid”和“NAT2”。如果报告了结核病患者中 NAT2 表型与异烟肼的药代动力学或疗效或安全性相关的研究，则选择这些研究。提取患者特征、NAT2 状态、异烟肼药代动力学参数、早期治疗失败和药物性肝损伤的发生率。如果数据以中位数给出，则将这些值标准化为平均值。纳入了 41 项药代动力学研究和 53 项安全性研究，但仅确定了 1 项疗效研究。在慢乙酰化者中，异烟肼的最大浓度平均值表示为超治疗浓度（成人：7.16±4.85μg/mL；儿童：6.43±3.87μg/mL）。在慢乙酰化者中，药物性肝损伤的平均发生率为 36.23±19.84%，与中间乙酰化者（19.49±18.20%）和快速乙酰化者（20.47±20.68%）显著不同。按大洲进行的亚组分析显示，亚洲慢乙酰化者的药物性肝损伤发生率最高（42.83±27.61%）。在一项研究中，基于基因型指导的异烟肼剂量给药可降低早期治疗失败的发生率。在大多数儿童和成人中，基于传统体重的异烟肼给药可产生治疗性异烟肼水平（除了慢乙酰化者）。药物性肝损伤在慢乙酰化者中更为常见。基于基因型的给药可能预防早期治疗失败。
