Decker C J, Laitinen L M, Bridson G W, Raybuck S A, Tung R D, Chaturvedi P R
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA.
J Pharm Sci. 1998 Jul;87(7):803-7. doi: 10.1021/js980029p.
Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The Ki value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 microM. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.
安普那韦（141W94、VX - 478、KVX - 478）在重组系统和人肝微粒体（HLM）中主要由细胞色素P450 3A4（CYP3A4）代谢。使用人肝微粒体在体外研究了酮康唑、特非那定、阿司咪唑、利福平、美沙酮和利福布汀对安普那韦代谢的影响。观察到酮康唑、特非那定和阿司咪唑抑制安普那韦的消耗，这与其对CYP3A4已知的特异性一致。在含有安普那韦的孵育体系中加入了HIV蛋白酶抑制剂茚地那韦、沙奎那韦、利托那韦和奈非那韦，以在体外研究HIV蛋白酶抑制剂之间的相互作用。观察到人肝微粒体中安普那韦代谢抑制的顺序为：利托那韦＞茚地那韦＞奈非那韦＞沙奎那韦。发现安普那韦介导的人肝微粒体中睾酮羟基化抑制的Ki值约为0.5微摩尔。研究表明，安普那韦对CYP3A4的抑制程度比利托那韦小得多，但比萨奎那韦大。安普那韦、奈非那韦和茚地那韦似乎对CYP3A4有中等程度的抑制作用，这表明存在一定数量的联合用药限制。
