Gene dose effect of NAT2 variants on the pharmacokinetics of isoniazid and acetylisoniazid in healthy Chinese subjects
Gene dose effect of NAT2 variants on the pharmacokinetics of isoniazid and acetylisoniazid in healthy Chinese subjects
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DOI：
10.1515/dmdi.2011.016
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发表时间：
2011-10-01
期刊：
影响因子：
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通讯作者：
Li Jinheng
中科院分区：
文献类型：
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作者：
Chen Bing;Cao Xiaomei;Li Jinheng
背景：本研究旨在阐明NAT2基因剂量效应及其对异烟肼（INH）及其代谢物乙酰异烟肼（AcINH）在中国受试者体内药代动力学的影响。方法：选取24例中国健康受试者，包括8例NAT2纯合野生型（wt/wt）、8例NAT2杂合突变型（m/wt）和8例NAT2纯合突变型（m/m）。受试者口服单剂量（300 mg） INH后（0-14 h）采血。用反相高效液相色谱法测定血浆中INH和AcINH的浓度。结果：给药后3 h， wt/wt、m/wt、m/m组AcINH、INH （R-A/I）比值分别为3.22 +/- 1.34、1.35 +/- 0.20、0.22 +/- 0.06 （p < 0.01）。3组INH的浓度-时间曲线下面积（AUC）分别为10.35 +/- 2.12、16.34 +/- 3.05、42.24 +/- 8.51 mg/h/L， AcINH的浓度-时间曲线下面积（AUC）分别为42.19 +/- 8.80、38.05 +/- 5.32、19.78 +/- 3.72 mg/h/L （p < 0.01）。药动学参数与活性NAT2基因数量呈良好的线性关系。结论：INH和AcINH的药代动力学存在明显的基因剂量效应。这一发现可能对INH结核的个性化治疗有价值。
Background: 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.Methods: 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.Results: 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.Conclusions: 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.