PDF(Pubmed)
Abstract：
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.
摘要：
N-乙酰转移酶2（NAT2）遗传多态性可能会改变异烟肼的代谢，从而导致毒性。我们回顾了NAT2基因型状态对药代动力学的影响，功效,以及异烟肼的安全性，结核病（TB）的治疗。系统地搜索发表在Scopus上的研究文章，PubMed,和Embase直到2023年8月31日，在没有过滤器或限制的情况下进行以下搜索词和布尔运算符：“异烟肼”和“NAT2。“如果报告了NAT2表型与异烟肼在结核病患者中的药代动力学或疗效或安全性，则选择了研究。患者特征,NAT2状态，异烟肼药代动力学参数，早期治疗失败，并提取药物性肝损伤的患病率。如果数据是作为中位数给出的，这些值被标准化为平均值.纳入了41项药代动力学研究和53项安全性研究，但只有一项疗效研究被确定。在慢速乙酰化剂中，异烟肼的平均最大浓度表示为成人（7.16±4.85μg/mL）和儿童（6.43±3.87μg/mL）的超治疗浓度。在慢乙酰化剂中，药物性肝损伤的平均患病率为36.23±19.84，与中间(19.49±18.20)和快速(20.47±20.68)乙酰化剂有显著差异。按大陆进行的亚组分析表明，亚洲慢乙酰化者的平均药物性肝损伤患病率最高（42.83±27.61）。在一项研究中，基因型指导的异烟肼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，传统的基于体重的异烟肼给药产生了治疗性异烟肼水平（缓慢乙酰化剂除外）。药物诱导的肝损伤在慢乙酰化剂中更常见。基因型指导的给药可以防止早期治疗失败。
