CYP3A4和CYP2B6诱导剂卡马西平的药代动力学及其药物相互作用潜力:基于生理的药代动力学建模方法

Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach.

作者信息

Fuhr Laura Maria, Marok Fatima Zahra, Hanke Nina, Selzer Dominik, Lehr Thorsten

机构信息

Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.

出版信息

Pharmaceutics. 2021 Feb 17;13(2):270. doi: 10.3390/pharmaceutics13020270.

Abstract

The anticonvulsant carbamazepine is frequently used in the long-term therapy of epilepsy and is a known substrate and inducer of cytochrome P450 (CYP) 3A4 and CYP2B6. Carbamazepine induces the metabolism of various drugs (including its own); on the other hand, its metabolism can be affected by various CYP inhibitors and inducers. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) parent-metabolite model of carbamazepine and its metabolite carbamazepine-10,11-epoxide, including carbamazepine autoinduction, to be applied for drug-drug interaction (DDI) prediction. The model was developed in PK-Sim, using a total of 92 plasma concentration-time profiles (dosing range 50-800 mg), as well as fractions excreted unchanged in urine measurements. The carbamazepine model applies metabolism by CYP3A4 and CYP2C8 to produce carbamazepine-10,11-epoxide, metabolism by CYP2B6 and UDP-glucuronosyltransferase (UGT) 2B7 and glomerular filtration. The carbamazepine-10,11-epoxide model applies metabolism by epoxide hydroxylase 1 (EPHX1) and glomerular filtration. Good DDI performance was demonstrated by the prediction of carbamazepine DDIs with alprazolam, bupropion, erythromycin, efavirenz and simvastatin, where 14/15 DDI AUC ratios and 11/15 DDI C ratios were within the prediction success limits proposed by Guest et al. The thoroughly evaluated model will be freely available in the Open Systems Pharmacology model repository.

摘要

抗惊厥药物卡马西平常用于癫痫的长期治疗,是细胞色素P450(CYP)3A4和CYP2B6已知的底物和诱导剂。卡马西平可诱导多种药物(包括其自身)的代谢;另一方面,其代谢可受到多种CYP抑制剂和诱导剂的影响。本研究的目的是建立一个基于生理的卡马西平及其代谢物卡马西平 - 10,11 - 环氧化物的药代动力学(PBPK)母体 - 代谢物模型,包括卡马西平自身诱导作用,用于药物 - 药物相互作用(DDI)预测。该模型在PK - Sim中开发,使用了总共92个血浆浓度 - 时间曲线(给药范围50 - 800 mg)以及尿中未变化排泄分数的测量值。卡马西平模型通过CYP3A4和CYP2C8进行代谢以产生卡马西平 - 10,11 - 环氧化物,通过CYP2B6和尿苷二磷酸葡萄糖醛酸基转移酶(UGT)2B7以及肾小球滤过进行代谢。卡马西平 - 10,11 - 环氧化物模型通过环氧化物水解酶1(EPHX1)和肾小球滤过进行代谢。通过预测卡马西平与阿普唑仑、安非他酮、红霉素、依非韦伦和辛伐他汀的DDI,证明了该模型具有良好的DDI预测性能,其中14/15的DDI AUC比值和11/15的DDI C比值在Guest等人提出的预测成功范围内。经过全面评估的模型将在开放系统药理学模型储存库中免费提供。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72c0/7922031/2d6bf7f1b7e4/pharmaceutics-13-00270-g001.jpg

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