Effect of serum lipids on the pharmacokinetics of atazanavir in hyperlipidemic rats
Effect of serum lipids on the pharmacokinetics of atazanavir in hyperlipidemic rats
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DOI：
10.1016/j.biopha.2009.01.008
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发表时间：
2009-11-01
影响因子：
7.5
通讯作者：
Takada, Kanji
中科院分区：
文献类型：
--
作者：
Fukushima, Keizo;Shibata, Masakazu;Takada, Kanji
阿扎那韦（Atazanavir， ATV）已成功用于HIV合并严重高脂血症（HL）患者；然而，对ATV在HL中的药代动力学知之甚少。本研究的目的是研究ATV在HL中的药代动力学。随着血脂的升高，HL大鼠的蛋白结合率（约97%）显著高于对照组（约87%）。以7 mg/kg剂量静脉（iv）、口服（po）和门内（ip）给予ATV后，HL大鼠AUCs分别为12.41、5.24和8.89 μ g/mL h，显著高于对照组（4.09、1.70和3.38 μ g/mL h）。尽管分布体积Vd（ss）减小，但终末半衰期（t(1/2)）较对照组有缩短的趋势，ATV在HL大鼠的肝脏分布增加了4.8倍。这些结果表明，ATV进入肝脏可能抵消Vd（ss）的下降。另一方面，生物利用度差异无统计学意义，淋巴运输到AUC的变化无统计学意义。综上所述，虽然ATV的蛋白结合率和AUC显著升高，但ATV在HL患者体内的药代动力学可能是耐受的。(C) 2009 Elsevier Masson SAS。版权所有。
Atazanavir (ATV) has been successfully used in HIV patients with severe hyperlipidemia (HL); however, little is known about the pharmacokinetics of ATV in HL. The aim of this study was to investigate the pharmacokinetics of ATV in HL. With the increase of serum lipids, the protein binding rate in HL rats (approximately 97%) was significantly higher than that in control (approximately 87%). After intravenous (iv), oral (po) and intraportal (ip) administration of ATV at a dosage of 7 mg/kg, AUCs in HL rats were 12.41, 5.24 and 8.89 mu g/mL h, respectively, and were significantly higher than those in control rats (4.09, 1.70 and 3.38 mu g/mL h). Despite the decrease of distribution volume (Vd(ss)), the terminal half-life (t(1/2)) in HL tended to be shorter than in control, and hepatic distribution of ATV in HL rats was 4.8-fold increases. These results suggested that the uptake of ATV into liver might counteract the decrease of Vd(ss). On the other hand, there was no significant difference in bioavailability, and the lymphatic transport to AUC showed no statistical change. In conclusion, although the protein binding rate and AUC were significantly increased, the pharmacokinetics of ATV might be tolerated in HL. (C) 2009 Elsevier Masson SAS. All rights reserved.