In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine
In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine
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DOI：
10.1124/jpet.102.047530
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发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Boyer, S
中科院分区：
文献类型：
--
作者：
Egnell, AC;Houston, B;Boyer, S
在体外，通常观察到CYP 3A 4底物的非典型（非米氏）动力学。如果在体内相关，细胞色素P450异源活化可能导致药物清除率增加。为了测试非典型细胞色素P450动力学可能的体内相关性，我们研究了异源活化在抗癫痫药非氨酯和卡马西平之间的治疗相关药物相互作用中的作用。在人肝微粒体和重组CYP 3A 4中，在两种药物的相关体内浓度下，非氨酯异源激活CYP 3A 4介导的卡马西平-10，11-环氧化物（卡马西平-ep）（卡马西平的主要代谢产物）的形成（在10 μ M卡马西平，1 mM非氨酯时最大激活率为98%）。根据人肝切片中的mRNA测量，非氨酯（50-500 μ M）不诱导CYP 3A 4。在人肝切片中，500 μ M非氨酯可抑制卡马西平-ep的进一步代谢38%。我们提出了一种方法来预测在稳态血浆浓度（Css）的母体药物和代谢物的变化，在体外异源激活和抑制数据，包括预测代谢分数的增加。进行了一项关于非氨酯对Css（卡马西平）体内影响的荟萃分析，以评价该方法。体外异源激活对Css（卡马西平）的预测效果与体内观察到的效果一致。结合异源活化对代谢为卡马西平-ep的部分的影响及其进一步代谢的抑制，预测Css（卡马西平-ep）的变化福尔斯在体内观察到的范围内。我们的研究结果强烈表明，在体内的CYP 3A 4的异源激活是一个可能的机制，临床观察到的药物相互作用之间的非氨酯和卡马西平。
Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4 substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could give rise to increased drug clearance. To test the possible in vivo relevance of atypical cytochrome P450 kinetics, we investigated the role of heteroactivation in the therapeutically relevant drug interaction between the anti-epileptics felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in vivo concentrations of both drugs ( maximum activation 98% at 10 muM carbamazepine, 1 mM felbamate). Felbamate (50-500 muM) did not induce CYP3A4, as based on mRNA measurements in human liver slices. The further metabolism of carbamazepine-ep was inhibited 38% by 500 muM felbamate) in human liver slices. We propose a methodology to predict changes in steady-state plasma concentrations (Css) of parent drug and metabolite from in vitro heteroactivation and inhibition data, including prediction of the increase in fraction metabolized. A meta-analysis of reported in vivo effects of felbamate on Css(carbamazepine) was performed to allow evaluation of this approach. The predicted effect of in vitro heteroactivation on Css(carbamazepine) corresponds well to that observed in vivo. Combining the effect of heteroactivation on the fraction metabolized to carbamazepine-ep, and inhibition of its further metabolism, predicts a change in Css(carbamazepine-ep) that falls within the range observed in vivo. Our results strongly suggest that in vivo heteroactivation of CYP3A4 is a possible mechanism of the clinically observed drug interaction between felbamate and carbamazepine.