Bing Chen, Xiaomeia Cao, Jinhenga Li
Department of Pharmacy, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Drug Metabol Drug Interact. 2011;26(3):113-8. doi: 10.1515/DMDI.2011.016.
The aim of this study was to elucidate the gene dose effect of NAT2 and the effect on the pharmacokinetics of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) in Chinese subjects.
A total of 24 healthy Chinese subjects, consisting of eight homozygous wild types (wt/wt), eight heterozygous mutants (m/wt) and eight homozygous mutants (m/m) for NAT2, were enrolled in the study. The blood samples (0-14 h) of the subjects were taken after oral administration of a single dose (300 mg) of INH. Concentrations of INH and AcINH in plasma were measured by a reversed-phase HPLC method.
The ratio of AcINH and INH (R(A/I)) 3 h post-dose of wt/wt, m/wt and m/m groups were 3.22 ± 1.34, 1.35 ± 0.20 and 0.22 ± 0.06, respectively (p<0.01). The area under concentration-time curve (AUC) values of three groups were 10.35 ± 2.12, 16.34 ± 3.05, 42.24 ± 8.51 mg/h/L for INH and 42.19 ± 8.80, 38.05 ± 5.32, 19.78 ± 3.72 mg/h/L for AcINH, respectively (p<0.01). There was a good linear relationship between pharmacokinetic parameters and the number of active NAT2 genes.
The results suggest that there is a conspicuous gene dose effect in the pharmacokinetics of INH and AcINH. This finding may be valuable in the personalized therapy of tuberculosis with INH.
本研究旨在阐明NAT2的基因剂量效应以及对中国受试者中异烟肼（INH）及其代谢产物乙酰异烟肼（AcINH）药代动力学的影响。
本研究共纳入24名健康中国受试者，其中包括8名NAT2纯合野生型（wt/wt）、8名杂合突变型（m/wt）和8名纯合突变型（m/m）。受试者口服单剂量（300mg）INH后采集血样（0 - 14小时）。采用反相高效液相色谱法测定血浆中INH和AcINH的浓度。
wt/wt、m/wt和m/m组给药后3小时的AcINH与INH比值（R(A/I)）分别为3.22±1.34、1.35±0.20和0.22±0.06（p<0.01）。三组INH的浓度-时间曲线下面积（AUC）值分别为10.35±2.12、16.34±3.05、42.24±8.51mg/h/L，AcINH的AUC值分别为42.19±8.80、38.05±5.32、19.78±3.72mg/h/L（p<0.01）。药代动力学参数与活性NAT2基因数量之间存在良好的线性关系。
结果表明INH和AcINH的药代动力学存在显著的基因剂量效应。这一发现可能对异烟肼治疗结核病的个体化治疗具有重要价值。
