Kumar Vikas, Brundage Richard C, Oetting William S, Leppik Ilo E, Tracy Timothy S
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Drug Metab Dispos. 2008 Jul;36(7):1242-8. doi: 10.1124/dmd.108.020396. Epub 2008 Mar 31.
The effects of genetic polymorphisms in drug-metabolizing enzymes (e.g., CYP2C9()3) on drug clearance have been well characterized but much less is known about whether these polymorphisms alter susceptibility to drug-drug interactions. Previous in vitro work has demonstrated that genotype-dependent inhibition of CYP2C9 mediated flurbiprofen metabolism, suggesting the possibility of genotype-dependent inhibition interactions in vivo. In the current study, flurbiprofen was used as a probe substrate and fluconazole as a prototypical inhibitor to investigate whether genotype-dependent inhibition of CYP2C9 occurs in vivo. From 189 healthy volunteers who were genotyped for CYP2C9 polymorphisms, 11 control subjects (CYP2C9()1/()1), 9 heterozygous and 2 homozygous for the CYP2C9()3 allele participated in the pharmacokinetic drug interaction study. Subjects received a single 50-mg oral dose of flurbiprofen alone or after administration of either 200 or 400 mg of fluconazole for 7 days using an open, randomized, crossover design. Flurbiprofen and fluconazole plasma concentrations along with flurbiprofen and 4'-hydroxyflurbiprofen urinary excretion were monitored. Flurbiprofen apparent oral clearance differed significantly among the three genotype groups (p < 0.05) at baseline but not after pretreatment with 400 mg of fluconazole for 7 days. Changes in flurbiprofen apparent oral clearance after fluconazole coadministration were gene dose-dependent, with virtually no change occurring in ()3/()3 subjects. Analysis of fractional clearances suggested that the fraction metabolized by CYP2C9, as influenced by genotype, determined the degree of drug interaction observed. In summary, the presence of CYP2C9(*)3 alleles (either one or two alleles) can alter the degree of drug interaction observed upon coadministration of inhibitors.
药物代谢酶（如CYP2C9(*3)）的基因多态性对药物清除率的影响已得到充分表征，但对于这些多态性是否会改变药物相互作用的易感性却知之甚少。先前的体外研究表明，CYP2C9介导的氟比洛芬代谢存在基因型依赖性抑制，这提示了体内存在基因型依赖性抑制相互作用的可能性。在本研究中，氟比洛芬被用作探针底物，氟康唑作为典型抑制剂，以研究体内是否发生CYP2C9的基因型依赖性抑制。在189名对CYP2C9多态性进行基因分型的健康志愿者中，11名对照受试者（CYP2C9(*1)/(*1)）、9名CYP2C9(*3)等位基因杂合子和2名纯合子参与了药代动力学药物相互作用研究。受试者采用开放、随机、交叉设计，单独口服50mg氟比洛芬，或在服用200mg或400mg氟康唑7天后服用。监测氟比洛芬和氟康唑的血浆浓度以及氟比洛芬和4'-羟基氟比洛芬的尿排泄。在基线时，三个基因型组的氟比洛芬表观口服清除率有显著差异（p<0.05），但在服用400mg氟康唑预处理7天后无差异。氟康唑合用后氟比洛芬表观口服清除率的变化呈基因剂量依赖性，在(*3)/(*3)受试者中几乎没有变化。分数清除率分析表明，受基因型影响，由CYP2C9代谢的分数决定了观察到的药物相互作用程度。总之，CYP2C9(*3)等位基因（一个或两个等位基因）的存在可改变抑制剂合用后观察到的药物相互作用程度。
