Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach.
Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach.
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DOI：
10.3390/pharmaceutics13020270
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发表时间：
2021-02-17
期刊：
影响因子：
5.4
通讯作者：
Lehr T
中科院分区：
文献类型：
--
作者：
Fuhr LM;Marok FZ;Hanke N;Selzer D;Lehr T
抗惊厥药卡马西平常用于癫痫的长期治疗，是细胞色素P450（CYP）3A 4和CYP 2B 6的已知底物和诱导剂。卡马西平可诱导多种药物（包括其自身）的代谢;另一方面，其代谢可受多种代谢抑制剂和诱导剂的影响。本研究的目的是建立卡马西平及其代谢物卡马西平-10，11-环氧化物的生理药代动力学（PBPK）母体代谢物模型，包括卡马西平自身诱导，用于药物相互作用（DDI）预测。该模型在PK-Sim中开发，共使用92个血药浓度-时间曲线（剂量范围50-800 mg）以及尿液测量中原型排泄分数。卡马西平模型应用CYP 3A 4和CYP 2C 8代谢产生卡马西平-10，11-环氧化物，CYP 2B 6和UDP-葡萄糖醛酸转移酶（UGT）2B 7代谢和肾小球滤过。卡马西平-10，11-环氧化物模型通过环氧化物羟化酶1（EPHX 1）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、依法韦仑和辛伐他汀的DDI，证明了良好的DDI性能，其中14/15 DDI AUClast比值和11/15 DDI Cmax比值在Guest等人提出的预测成功限度内。将在开放系统药理学模型库中免费提供经过全面评价的模型。
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 AUClast ratios and 11/15 DDI Cmax 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.
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影响因子：
4.6
作者：
Annaert, Pieter;Brouwers, Joachim;Augustijns, Patrick
通讯作者：
Augustijns, Patrick
影响因子：
3.9
作者：
Fahmi, Odette A.;Kish, Mary;Obach, R. Scott
通讯作者：
Obach, R. Scott
影响因子：
5.6
作者：
Adiwidjaja, Jeffry;Boddy, Alan V.;McLachlan, Andrew J.
通讯作者：
McLachlan, Andrew J.
影响因子：
3.4
作者：
Cazali, N;Tran, A;Pons, G
通讯作者：
Pons, G
DOI：
10.1124/jpet.106.112136
发表时间：
2007-01-01
影响因子：
3.5
作者：
Faucette, Stephanie R.;Zhang, Tong-Cun;Wang, Hongbing
通讯作者：
Wang, Hongbing