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首页> 外文期刊>European journal of pharmaceutical sciences >Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects
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Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects

机译：牛毒素的人口药代动力学及其在健康受试者中的代谢物10-羟基葡萄球菌病

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摘要

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n = 12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300 mg b.i.d. and 80 mg t.i.d., respectively. Blood samples (n = 185) were collected over a period of 12 h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9 L/h (69.5-100.3) for oxcarbazepine and 2.0 L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131 L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6 L (14.4-32.8) vs. 31.7 L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition.
机译：表明氧毒脂动物用于治疗部分或广义滋补克隆癫痫发作。大多数被吸收的氧泌虫毒脂肠转化为其活性代谢物，10-羟基氨基甲酸（MHD），其可以作为R - （ - ） - 和S - （+） - MHD对映体。在这里，我们描述了p-糖蛋白（P-GP）抑制剂维拉帕米对氧化碱和MHD对映体的布置的影响，两者都是P-GP基材。健康受试者（n = 12）被随机与氧碱或牛毒脂动物组合在300mg B.I.D的剂量下与维拉帕米合并。分别为80 mg t.i.d.。收集血毒败死后12小时的时间（n = 185）。使用使用元分析方法使用非线性混合效果建模开发了集成的PK模型。通过具有吸收转动隔室的两个隔室模型描述了Oxcarbazepine的药代动力学和一阶消除。通过单室分布模型表征了MHD对映体的浓度 - 时间谱。许可估计（95％CI）为84.9L / h（69.5-100.3），用于氧化碱和2.0L / h（1.9-2.1），适用于MHD对映体。与R - （ - ） - 和S - （+） - MHD（23.6L（14.4-32.8）与31.7 L（22.5- 40.9）分别）。维拉帕米的共同施用导致氧化碱的表观生物有效性增加12％（10-28），但不影响父母或代谢物间隙。尽管在施用维拉帕米后，尽管有可比的系统性水平的胃和MHD，但在糖蛋白抑制后，脑暴露于两部分的脑暴露的差异。

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