In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19.
In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19.
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DOI：
10.2133/dmpk.dmpk-12-rg-124
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发表时间：
2013
影响因子：
2.1
通讯作者：
Desta Z
中科院分区：
文献类型：
--
作者：
Xu C;Desta Z
为了定量预测药物相互作用与依法韦仑为基础的抗艾滋病病毒治疗，我们评估了可逆的和时间依赖性的依法韦仑对8个细胞色素P450（CYP 1A 1）酶在体外的抑制。目前的研究表明，依法韦仑是HLM中CYP 2B 6的强效竞争性抑制剂（平均Ki = 1.68 μM），并表达CYP 2B 6（Ki = 1.38 μM）。在合并的HLM（Ki = 4.78 μM）和具有CYP 2C 8 *3/*3基因型的HLM（Ki = 4.80 μM）中观察到依法韦仑对CYP 2C 8的中度抑制。依法韦仑是CYP 2C 9（Ki= 19.46 μM）和CYP 2C 19（Ki= 21.31 μM）的中度抑制剂;以及CYP 3A（Ki= 40.33 μM）的弱抑制剂。未观察到对CYP 1A 2、CYP 2A 6或CYP 2D 6的明显抑制。本研究中未观察到依法韦仑对CYP的时间依赖性抑制。定量预测显示，依法韦仑单次给药可显著减缓主要由CYP 2B 6、CYP 2C 19或两种酶清除的药物的消除，还可使某些前药（如氯吡格雷和氯胍）活性代谢物的血浆浓度-时间曲线下面积（AUC）降低30%。依非韦仑长期给药可能使稳态时CYP 2C 8和CYP 2C 9底物的AUC增加约3.5 ~ 4.4倍和1.7 ~ 2.0倍，具体取决于底物。
In order to quantitatively predict drug interactions associated with efavirenz-based anti-HIV therapy, we evaluated reversible and time-dependent inhibitions of efavirenz on eight cytochrome P450 (CYP) enzymes in vitro. Present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 in HLMs (average Ki = 1.68 μM) and expressed CYP2B6 (Ki = 1.38 μM). Moderate inhibition of CYP2C8 by efavirenz was observed in pooled HLMs (Ki = 4.78 μM) and HLMs with CYP2C8*3/*3 genotype (Ki = 4.80 μM). Efavirenz was a moderate inhibitor of CYP2C9 (Ki= 19.46 μM) and CYP2C19 (Ki= 21.31 μM); and a weak inhibitor of CYP3A (Ki= 40.33 μM). No appreciable inhibition was observed on CYP1A2, CYP2A6 or CYP2D6. No time-dependent inhibition of the CYPs by efavirenz was observed in this study. Quantitative predictions showed that single dose of efavirenz may substantially slow the elimination of drugs predominately cleared by CYP2B6, CYP2C19 or by both enzymes and may also lower the area under the plasma concentration time curve (AUC) of active metabolites of some pro-drugs (e.g. clopidogrel and proguanil ) by up to 30%. Depending on substrates, chronic administration of efavirenz may increase the AUC of CYP2C8 and CYP2C9 substrates about 3.5 ~ 4.4-fold and 1.7 ~ 2.0-fold at steady state.
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影响因子：
3.9
作者：
Foti, Robert S.;Wahlstrom, Jan L.
通讯作者：
Wahlstrom, Jan L.
影响因子：
2.6
作者：
di Iulio, Julia;Fayet, Aurelie;Telenti, Amalio
通讯作者：
Telenti, Amalio
影响因子：
20.3
作者：
Hulot, Jean-Sebastien;Bura, Alessandra;Gaussem, Pascale
通讯作者：
Gaussem, Pascale
影响因子：
3.9
作者：
Boulenc, Xavier;Djebli, Nassim;Hurbin, Fabrice
通讯作者：
Hurbin, Fabrice
DOI：
10.1097/qad.0b013e3283319908
发表时间：
2009-10-23
期刊：
AIDS (London, England)
影响因子：
--
作者：
Kwara A;Lartey M;Sagoe KW;Kenu E;Court MH
通讯作者：
Court MH