Kirchheiner Julia, Meineke Ingolf, Müller Gunnar, Roots Ivar, Brockmöller Jürgen
Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University Berlin, Berlin, Germany.
Pharmacogenetics. 2002 Oct;12(7):571-80. doi: 10.1097/00008571-200210000-00010.
In-vitro data indicated a contribution of cytochrome P450 enzymes 1A2, 3A4, 2C9, 2C19 and 2D6 to biotransformation of doxepin. We studied the effects of genetic polymorphisms in CYP2D6, CYP2C9 and CYP2C19 on E- and Z-doxepin pharmacokinetics in humans. Doxepin kinetics was studied after a single oral dose of 75 mg in healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/3. E-, Z-doxepin and -desmethyldoxepin were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics and by population pharmacokinetic modeling considering effects of genotype on clearance and bioavailability. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271), and 127 (124-139) l h(-1) in EMs, IMs and PMs of CYP2D6. In addition, EMs had about 2-fold lower bioavailability compared with PMs indicating significant contribution of CYP2D6 to E-doxepin first-pass metabolism. E-doxepin oral clearance was also significantly lower in carriers of CYP2C93/*3 (238 l h(-1) ). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l h(-1) in CYP2C19 PMs compared with 191 l h(-1) in EMs). The area under the curve (0-48 h) of the active metabolite -desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35, and 1.28 nmol l h(-1) in PMs, IMs, and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The CYP2D6 polymorphism had a major impact on E-doxepin pharmacokinetics and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.
体外数据表明细胞色素P450酶1A2、3A4、2C9、2C19和2D6参与了多塞平的生物转化。我们研究了CYP2D6、CYP2C9和CYP2C19基因多态性对人E型和Z型多塞平药代动力学的影响。对健康志愿者单次口服75 mg多塞平后的药代动力学进行了研究，这些志愿者的基因型分别为CYP2D6和CYP2C19底物的广泛代谢者（EM）、中间代谢者（IM）和慢代谢者（PM），以及CYP2C9基因型为*3/3的慢代谢者。采用高效液相色谱法对血浆中的E型、Z型多塞平和去甲基多塞平进行定量。通过非参数药代动力学和统计学方法以及考虑基因型对清除率和生物利用度影响的群体药代动力学模型对数据进行分析。CYP2D6的EM、IM和PM中E型多塞平的平均清除率（95%置信区间）分别为406（390 - 445）、247（241 - 271）和127（124 - 139）l h⁻¹。此外，EM的生物利用度比PM低约2倍，表明CYP2D6对E型多塞平首过代谢有显著贡献。CYP2C93/*3携带者中E型多塞平的口服清除率也显著降低（238 l h⁻¹）。CYP2C19参与Z型多塞平的代谢，口服清除率相差2.5倍（CYP2C19的PM中为73 l h⁻¹，而EM中为191 l h⁻¹）。活性代谢产物去甲基多塞平的曲线下面积（0 - 48小时）取决于CYP2D6基因型，CYP2D6的PM、IM和EM中的中位数分别为5.28、1.35和1.28 nmol l h⁻¹。这些基因多态性酶对人多塞平的生物转化表现出高度立体选择性作用。CYP2D6多态性对E型多塞平药代动力学有重大影响，当使用常用推荐剂量治疗时，CYP2D6的PM可能有更高的药物不良反应风险。
