Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6
Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6
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DOI：
10.1097/00008571-200310000-00005
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发表时间：
2003-10-01
期刊：
影响因子：
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通讯作者：
Brockmöller, J
中科院分区：
文献类型：
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作者：
Kirchheiner, J;Klein, C;Brockmöller, J
安非他酮用于治疗抑郁症和戒烟。细胞色素 P450 2B36 (CYP2B6) 的遗传多态性可能会导致安非他酮药代动力学的变异，因为已知羟基化是由 CYP2B6 介导的。安非他酮可能是人类 CYP2B6 活性的探针药物。对 121 名健康男性志愿者单次口服 150 mg 剂量后的安非他酮药代动力学进行了研究。采用聚合酶链式反应和限制性片段长度多态性分析氨基酸多态性R22C、Q172H、S259R、K262R和R487C，并采用高效液相色谱法测定血浆浓度。通过非参数方法和群体药代动力学模型进行药代动力学分析。检测到安非他酮和羟基安非他酮动力学参数的单峰分布，平均（范围）曲线下面积（AUC）为 3.64（0.89-8.14）μmol。 h/l 对于安非他酮和 25.5 (6.72-75.3) mumol 。 h/l 为羟基安非他酮。群体动力学分析显示，通过 CYP2B6 等位基因 * 1、* 2、* 5 和 * 6 的安非他酮总清除率没有差异，但通过等位基因 * 4 的清除率是野生型等位基因 * 1 的 1.66 倍（P = 0.001）。与安非他酮的高清除率相对应，与所有其他基因型相比，CYP2B6 基因型 * 1/*4 的携带者具有显着更高的羟基安非他酮 C-max (P = 0.03)。安非他酮和羟基安非他酮动力学的变异性中只有一小部分可以通过已知的 CYP2B6 氨基酸变体，特别是 CYP2B6*4 等位基因来解释。该等位基因的作用也应在其他 CYP2B6 底物中进行研究，包括环磷酰胺、氟烷、米安色林、异丙嗪和丙泊酚。药物遗传学 13:619-626 (C) 2003 Lippincott Williams Wilkins。
Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B36 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by nonparametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) mumol . h/l for bupropion and 25.5 (6.72-75.3) mumol . h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles * 1, *2, *5 and * 6 did not differ, but clearance via allele * 4 was 1.66-fold higher compared to wild-type allele * 1 (P = 0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype * 1/*4 had significantly higher C-max of hydroxybupropion compared to all other genotypes (P = 0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol. Pharmacogenetics 13:619-626 (C) 2003 Lippincott Williams Wilkins.