描述人类细胞色素P450的选择性和机制抑制人类免疫缺陷virus-protease抑制剂甲磺酸奈非那韦。
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Lillibridge JH,梁BH,克尔BM,韦伯,夸脱B, Shetty BV,李CA
描述人类细胞色素P450的选择性和机制抑制人类免疫缺陷virus-protease抑制剂甲磺酸奈非那韦。
药物金属底座Dispos。1998年7月,26 (7):609 - 16。
- PubMed ID
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9660842 (在PubMed]
- 文摘
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体外研究与人类肝脏微粒体P450探针底物进行描述选择性和甲磺酸奈非那韦的细胞色素P450抑制机制。在治疗浓度(稳态血浆浓度大约4 microM)、奈非那韦是一种竞争性抑制剂的睾丸激素6 beta-hydroxylase (CYP3A4) Ki浓度4。8 microM。supratherapeutic浓度,奈非那韦竞争性抑制右美沙芬O-demethylase (CYP2D6) S-mephenytoin 4-hydroxylase (CYP2C19)和非那西汀O-deethylase (CYP1A2) Ki浓度为68,126,和190 microM,分别。奈非那韦没有明显抑制甲苯磺丁脲4-hydroxylase (CYP2C9),紫杉醇6α-羟化酶(CYP2C8),或chlorzoxaxone 6 beta-hydroxylase (CYP2E1)活动。奈非那韦的抑制效力对CYP3A4建议的可能性体内抑制同种型,而体内抑制其他p450酶类被认为是不可能的。在一个序列交叉研究在12个健康的志愿者,奈非那韦抑制CYP3A的消除衬底terfenadine和羧酸盐terfenadine代谢物。6基本以24小时为尿复苏beta-hydroxycortisol奈非那韦治疗期间平均减少了27%,符合CYP3A奈非那韦的抑制。奈非那韦体外抑制CYP3A4的NADPH-dependent要求催化代谢物或代谢中间物的形成。奈非那韦的苯邻二酚代谢物(M3)被认为是不太可能负责抑制儿茶酚的除了O-methyl转移酶,S-adenosyl蛋氨酸,抗坏血酸混合预培养没有防止睾丸激素6 beta-hydroxylase活动的损失。 Also, the addition of M3 to human liver microsomes did not inhibit CYP3A4. Although incubations with nelfinavir showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated that inhibition was reversible. Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control. Glutathione, N-acetylcysteine, and catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450.
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药物 酶 类 生物 药理作用 行动 奈非那韦 细胞色素P450 2 d6 蛋白质 人类 没有抑制剂细节 奈非那韦 细胞色素P450 3 a4 蛋白质 人类 没有底物抑制剂细节 - 药物的相互作用Learn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
