A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on CYP3A4
A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on CYP3A4
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DOI：
10.1111/j.1528-1167.2007.00924.x
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发表时间：
2007-03-01
期刊：
影响因子：
5.6
通讯作者：
Damkier, Per
中科院分区：
文献类型：
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作者：
Andreasen, Astrid-Helene;Brosen, Kim;Damkier, Per
目的：卡马西平(CBZ)和奥卡西平(OXCZ)是公认的通过细胞色素P3A4代谢的药物。间接相互作用研究和临床经验表明，CBZ在这方面比OXCZ具有更强的潜力。然而，这从来没有受到过直接的比较研究。我们在健康志愿者中进行了一项研究，以奎尼丁的代谢为生物标记物，研究卡马西平和奥克西平对细胞色素P3A4活性的相对诱导作用。方法：10名健康男性志愿者参加了一项开放的随机交叉研究，试验分为两个阶段，中间隔着4周的洗脱期。受试者每天口服奥昔洛韦1200 mg，疗程17天；口服卡马西平800 mg，疗程17天。在基线和CBZ和OXCZ给药后，单次口服200毫克奎尼丁。结果：治疗后3-羟基奎尼丁的形成清除率较治疗前分别增加89%(CI：36~164，p=0.0022)和181%(CI：120~260，p<；0.0001)。CBZ的相对诱导效应比OXCZ高46%。AUC比率增加161%(CI：139187，P<；0.0001)和222%(CI：192-257，P<；0.0001)(CBZ)。奎尼丁Cmax平均下降29%(CI：16-40，p=0.0018)和33%(CI：18-45，p=0.0020)。T-1/2平均下降12%(CI：6-17，P<；0.0014)和32%(CI：25-38，P<；0.0001)。结论：OXCZ和CBZ均有显著的临床诱导作用。CBZ的诱导效果比OXCZ高约46%，这一差异可能具有临床意义。
Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction.Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine.Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36-164; p = 0.0022) and 181% (CI: 120-260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139-187, p < 0.0001) (OXCZ) and 222% (CI: 192-257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16-40, p = 0.0018) (OXCZ) and 33% (CI: 18-45, p = 0.0020) (CBZ). T-1/2 decreased by means of 12% (CI: 6-17, p < 0.0014) (OXCZ) and 32% (CI: 25-38, p < 0.0001) (CBZ). t(max) was not changed in either period.Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance.