利托那韦
尿
代谢物
口服
药代动力学
新陈代谢
小猎犬
粪便
药理学
化学
内分泌学
内科学
生物
医学
免疫学
微生物学
人类免疫缺陷病毒(HIV)
病毒载量
抗逆转录病毒疗法
作者
Jon F. Denissen,Brian A. Grabowski,Marianne K. Johnson,Alex Buko,Dale J. Kempf,Samuel Thomas,Bruce W. Surber
出处
期刊:PubMed
日期:1997-04-01
卷期号:25 (4): 489-501
被引量:50
摘要
The metabolism and disposition of [14C]ritonavir (ABT-538, NOR-VIR), a potent, orally active HIV-1 protease inhibitor, were investigated in male and female Sprague-Dawley rats, beagle dogs, and HIV-negative male human volunteers. Rats and dogs received a 5 mg/kg iv, 20 mg/kg oral or 20 mg/kg intraduodenal dose, whereas humans received a single 600-mg liquid oral dose. Ritonavir was cleared primarily via hepatobiliary elimination in all three species. After iv or oral dosing in either rats or dogs, > 92% of the dose was recovered in rat and dog feces and < or = 4% was recovered in the urine. Humans excreted 86.3% of the oral dose in feces and 11.3% in urine over 6 days. Bile-exteriorized rats and dogs excreted 85.5% and 39.8%, respectively, of the iv dose in bile, with < 3% recovered in urine. Radio-HPLC analysis of bile, feces, and urine from all three species indicated extensive metabolism of ritonavir to a number of oxidative metabolites, some being species-specific, and all involving metabolism at the terminal functional groups of the molecule. Glucuronide metabolites were observed in dog only. Plasma radioactivity consisted predominantly of unchanged parent drug in all three species. M-2, the product of hydroxylation at the methine carbon of the terminal isopropyl moiety of ritonavir, was the only metabolite present in human plasma and made up 30.4% of the total dose recovered in human excreta over 6 days. Tissue distribution of ritonavir in rat was widespread, with good distribution into lymphatic tissue but low CNS penetration. Plasma protein binding of ritonavir was high (96-99.5%) in all species and was nonsaturable in humans at concentrations up to 30 micrograms/ml. Partitioning into the formed elements of whole blood was minimal.
科研通智能强力驱动
Strongly Powered by AbleSci AI