Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
Geneva-Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland.
Clin Pharmacol Ther. 2018 Jul;104(1):148-157. doi: 10.1002/cpt.889. Epub 2017 Nov 6.
We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.
我们研究了在 CYP2D6 抑制剂存在的情况下，携带无功能等位基因的 CYP2D6 广泛代谢者是否有更高的表型转化为不良代谢者的风险。本试验共有 17 名纯合子携带两个完全功能等位基因的个体和 17 名杂合子携带一个完全功能和一个无功能等位基因的个体参与。在每个三个研究阶段中，给予右美沙芬 5mg 和曲马多 10mg。在第 2 阶段给予度洛西汀 60mg 和在第 3 阶段给予帕罗西汀 20mg 来抑制 CYP2D6。与度洛西汀相比，在杂合子中观察到更高的表型转化为中间代谢物的发生率（71%比 25%，P=0.009）和与帕罗西汀相比转化为不良代谢者的发生率（94%比 56%，P=0.011）。与杂合子相比，在纯合子中右美沙芬与帕罗西汀之间的药物相互作用的幅度更高（14.6 比 8.5，P < 0.028）。我们的研究表明，遗传广泛代谢者可能不是一个同质群体，在临床实践中解决药物相互作用时应考虑可用的遗传数据。
