Aarnoutse Rob E, Kleinnijenhuis Johanneke, Koopmans Peter P, Touw Daan J, Wieling Jaap, Hekster Yechiel A, Burger David M
Departments of Clinical Pharmacy and General Internal Medicine, Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
Clin Pharmacol Ther. 2005 Dec;78(6):664-74. doi: 10.1016/j.clpt.2005.09.001.
In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study.
This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir.
Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer.
Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.
在人类免疫缺陷病毒感染的治疗中，蛋白酶抑制剂利托那韦以低剂量（每日两次，每次100毫克）使用，以抑制细胞色素P450（CYP）3A4，从而提高同时服用的蛋白酶抑制剂的血浆浓度。当以治疗剂量（每日两次，每次600毫克）应用时，利托那韦也会抑制CYP2D6。低剂量利托那韦对CYP2D6的影响尚不清楚，本研究对此进行了调查。
这是一项单组、两阶段、固定顺序的研究，纳入了13名CYP2D6的广泛代谢者的健康男性志愿者。第一阶段通过评估单剂量去甲丙咪嗪的药代动力学以及用右美沙芬进行代谢表型分析来检测基线CYP2D6活性。在第二阶段，参与者每日两次服用100毫克利托那韦，持续2周，然后在有利托那韦的情况下重复评估去甲丙咪嗪的药代动力学和右美沙芬代谢表型。
低剂量利托那韦（每日两次，每次100毫克）显著增加了单剂量去甲丙咪嗪的暴露量，从时间0到无穷大的浓度-时间曲线下面积的去甲丙咪嗪几何平均比值（有利托那韦/无利托那韦）为1.26（95%置信区间，1.13 - 1.40），表明了这一点（P <.001）。低剂量利托那韦的共同给药并未显著影响右美沙芬/右啡烷尿代谢比值，也未使任何广泛代谢者转变为慢代谢者。
以去甲丙咪嗪作为指标底物评估，低剂量利托那韦（每日两次，每次100毫克）对广泛代谢者的CYP2D6活性有适度的抑制作用。以右美沙芬/右啡烷代谢比值作为CYP2D6活性指标时，这种作用并不明显。预计低剂量利托那韦对CYP2D6的影响不会要求对CYP2D6底物进行标准剂量降低。
