抗SARS化合物niclosamide與其結構類似物之藥物動力特性   全文下載

Pharmacokinetics of Anti-SARS-CoV Agent Niclosamide and Its Analogs in Rats

Niclosamide具有抑制SARS-CoV病毒複製的作用。本實驗之目的為評估Niclosamide及其結構類似物（BPR1H366與BPR1H369）於大鼠體內經靜脈及口服途徑單一劑量投藥後之藥物動力學分析。靜脈注射（2-mg/kg）給藥的結果顯示，Niclosamide，BPR1H366與 BPR1H369的CL與Vss分別為20.0 ± 2.9、26.7 ± 4.4、39.4 ± 6.7 mL/kg/min及 0.9 ± 0.4、0.3 ± 0.1、1.1 ± 0.2 L/kg。BPR1H366與BPR1H369的t1/2皆短於Niclosamide。AUC依序是：Niclosamide＞BPR1H366＞BPR1H369。口服（5-mg/kg）藥物後，三個化合物皆很快地被吸收，其中以Niclosamide有最高的Cmax。Niclosamide，BPR1H366與BPR1H369的口服生體可用率分別為 10%、12% 和15%。我們在大鼠的藥物動力學研究結果顯示，niclosamide或其化學類似物可能被用為SARS的治療，惟在人體的藥物動力性質須進一步探討。

Niclosamide has been demonstrated with inhibitory activity on the replication of SARS-CoV in Vero E6 cells. This study examined the pharmacokinetics and oral bioavailability of niclosamide and its two analogs, BPR1H366 and BPR1H369, in male Sprague-Dawley rats. After a single 2-mg/kg intravenous dose, the total body clearance (CL) of niclosamide, BPR1H366 and BPR1H369 was 20.0 ± 2.9, 26.7 ± 4.4 and 39.4 ± 6.7 mL/kg/min, and the volume of distribution at steady state (VSS) was 0.9 ± 0.4, 0.3 ± 0.1 and 1.1 ± 0.2 L/kg, respectively. The half-life (t1/2) of BPR1H366 and BPR1H369 was 2.6 ± 0.3 and 3.7 ± 1.1 hr, respectively, shorter than 6.7 ± 2.0 hr of niclosamide. The AUC was 1413 ± 118, 1019 ± 203 and 750 ± 113 ng/mL × hr for niclosamide, BPR1H366 and BPR1H369, respectively. After a single 5-mg/kg oral dose, all three compounds were rapidly absorbed. Niclosamide showed the highest Cmax of 354 ± 152 ng/mL within 30 min after oral gavage. The oral bioavailability of niclosamide, BPR1H366 and BPR1H369 was 10%, 12% and 15%, respectively. Our results demonstrated that the extents of drug exposure of the three compounds were comparable in rats. The pharmacokinetic properties of the compounds in humans are needed to be determined before their potential uses in SARS-CoV infected patients.