Merry C, Barry M G, Mulcahy F, Ryan M, Heavey J, Tjia J F, Gibbons S E, Breckenridge A M, Back D J
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
AIDS. 1997 Mar 15;11(4):F29-33. doi: 10.1097/00002030-199704000-00001.
The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients.
SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily.
Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography.
For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001) ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006].
For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.
参与蛋白酶抑制剂代谢的最重要的肝脏酶是细胞色素P450 3A4（CYP3A4）。利托那韦（RIT）是一种强效的CYP3A4抑制剂，可抑制健康志愿者体内的沙奎那韦（SQV）代谢。在本研究中，我们调查了在HIV感染患者中单独使用SQV以及与RIT联合使用时SQV的动力学情况。
在7例患有晚期HIV疾病的患者中测定了SQV的药代动力学。在单独每日3次服用600 mg SQV以及与每日2次服用300 mg RIT联合使用后，分两次获得稳态SQV曲线。
在给药后0、1、2、4、6和8小时采集血样。离心后，将分离出的血浆在58℃加热至少30分钟以使HIV失活，并储存在-80℃直至使用高效液相色谱法进行分析。
对于单独接受SQV治疗的患者，SQV浓度-时间曲线下面积（AUC0-8h）存在12倍的变异性，范围为293至3446 ng·h/ml。与RIT联合使用时，SQV的最大血浆浓度显著增加[中位数（范围），146（57-702）对4795（1420-15810）ng/ml；约95%置信区间（CI），2988-681；P = 0.0006，曼-惠特尼U检验]。在有RIT存在的情况下，SQV的AUC0-8h也显著增加[中位数（范围），470（29-3446）对27458（7357-108001）ng·h/ml；约95%CI，16628-35111；P = 0.0006]。
对于一些患者，每日3次服用600 mg SQV会导致SQV血浆水平非常低，可能几乎没有抗病毒效果。SQV与RIT联合使用会导致由酶抑制介导的显著药物相互作用，使患者暴露于非常高的SQV浓度和潜在毒性中。如果考虑SQV加RIT的联合治疗，则应大幅降低SQV的剂量。
