Dalén P, Alvan G, Wakelkamp M, Olsen H
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Pharmacogenetics. 1996 Oct;6(5):387-94. doi: 10.1097/00008571-199610000-00002.
Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.
卡立普多是一种肌肉松弛镇痛药，它有一个活性代谢物即甲丙氨酯。我们对15名健康志愿者进行了一项开放的三部分单剂量给药研究：5名苯妥英钠慢代谢者、5名异喹胍慢代谢者和5名两种底物的快代谢者。目的是研究卡立普多和甲丙氨酯的消除是否依赖于苯妥英钠和异喹胍的两种代谢多态性。受试者在不同时间分别口服单剂量700毫克卡立普多和400毫克甲丙氨酯。卡立普多的处置与苯妥英钠羟基化表型明显相关。苯妥英钠慢代谢者中卡立普多的平均血清清除率比快代谢者低四倍，这证实了我们先前研究中的假设，即卡立普多的N-脱烷基化与苯妥英钠羟基化多态性共分离。然而，两组中甲丙氨酯的平均血清清除率没有差异。此外，异喹胍羟基化多态性也不影响卡立普多或甲丙氨酯的消除。因此，苯妥英钠慢代谢者代谢卡立普多的能力较低，如果用常规剂量的卡立普多治疗，可能会增加出现如嗜睡和低血压等浓度依赖性副作用的风险。
