Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats
Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats
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DOI：
10.1124/dmd.105.006536
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发表时间：
2006-04-01
影响因子：
3.9
通讯作者：
Leggas, M
中科院分区：
文献类型：
--
作者：
Anderson, BD;May, MJ;Leggas, M
用于治疗人类免疫缺陷病毒（HIV）感染的高活性抗逆转录病毒疗法中使用的大多数逆转录酶和蛋白酶抑制剂对大脑的渗透性较差，这引起了人们的担忧，即大脑可能是耐药HIV变体发展的避难所。本研究探讨了zosuquidar剂量与血浆和脑浓度之间的关系，以及这种选择性P-糖蛋白抑制剂对HIV蛋白酶抑制剂奈非那韦通过静脉输注维持在大鼠稳态的中枢神经系统渗透的影响。输注奈非那韦（10 mg/kg/h）长达10 h，同时或不同时在4 h时静脉推注2、6或20 mg/kg佐舒喹达。分析脑组织和血浆中的两种药物浓度。脑组织/血浆奈非那韦浓度比（未校正血管贡献）随佐舒喹达剂量呈非线性增加，从不存在佐舒喹达时的0.06 +/- 0.03和2 mg/kg佐舒喹达后2 - 6 h的0.09 +/- 0.02增加至6 mg/kg后的0.85 +/- 0.19和20 mg/kg佐舒喹达后的1.58 +/- 0.67。Zosuquidar脑组织/血浆浓度比显示出相似的突然增加，从2 mg/kg剂量后的2.8 +/- 0.3增加至6和20 mg/kg剂量后的15。显著增强脑内奈非那韦摄取所需的佐舒喹达血药浓度的表观阈值似乎接近患者中佐舒喹达重复给药后文献中报告的最大耐受剂量相关血药浓度。
Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma were analyzed for both drug concentrations. Brain tissue/plasma nelfinavir concentration ratios (uncorrected for the vascular contribution) increased nonlinearly with zosuquidar dose from 0.06 +/- 0.03 in the absence of zosuquidar and 0.09 +/- 0.02 between 2 and 6 h after 2 mg/kg zosuquidar to 0.85 +/- 0.19 after 6 mg/kg and 1.58 +/- 0.67 after 20 mg/kg zosuquidar. Zosuquidar brain tissue/plasma concentration ratios exhibited a similar abrupt increase from 2.8 +/- 0.3 after a 2 mg/kg dose to similar to 15 after the 6 and 20 mg/kg doses. The apparent threshold in the plasma concentration of zosuquidar necessary to produce significant enhancement in brain uptake of nelfinavir appears to be close to the plasma concentrations associated with the maximum tolerated dose reported in the literature after repeated dosing of zosuquidar in patients.