González-Martin G, Paulos C, Guevara A, Ponce G
Department of Pharmacy, Faculty of Chemistry, Pontifical Catholic University of Chile, Santiago.
J Pharm Pharmacol. 1994 May;46(5):356-9. doi: 10.1111/j.2042-7158.1994.tb03812.x.
Nifurtimox disposition was investigated using the rat isolated perfused-liver method after administration of 25 micrograms mL-1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at various times. Biliary excretion was also measured. The drug concentration profile underwent a biexponential decline over the 2-h study period, with a terminal half-life of 62.76 +/- 17.56 min. Nifurtimox is a high clearance compound (15.23 +/- 5.53 mL min-1). The extraction ratio was 0.621 +/- 0.159. Biliary excretion accounted for 0.05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minimal fraction of unchanged nifurtimox was recovered from the perfusate. Nifurtimox activity against Trypanosoma cruzi (clone CA-1) during the perfusion was also determined. Epimastigotes isolated from continuous culture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27 degrees C, the parasite number in each well was counted under a microscope. From 0 to 75 min after the perfusion, the anti-trypanosomal activity decreased, but an increase in activity was observed at the later times. These findings show that active metabolites are formed during the perfusion.
在给予25微克/毫升硝呋莫司后，采用大鼠离体灌注肝脏法研究硝呋莫司的处置情况，并通过在不同时间分析灌注液样本监测其消失情况。同时也测定了胆汁排泄。在2小时的研究期间，药物浓度曲线呈双指数下降，终末半衰期为62.76±17.56分钟。硝呋莫司是一种高清除率化合物（15.23±5.53毫升/分钟）。提取率为0.621±0.159。胆汁排泄占给药剂量的0.05%，其余为高极性代谢物。到2小时时，从灌注液中回收的未变化硝呋莫司的比例极小。还测定了灌注期间硝呋莫司对克氏锥虫（克隆CA - 1）的活性。从连续培养物中分离出的无鞭毛体在微量滴定板中于不同灌注时间暴露于灌注液样本。在27℃孵育72小时后，在显微镜下计数每个孔中的寄生虫数量。灌注后0至75分钟，抗锥虫活性降低，但在随后的时间观察到活性增加。这些发现表明在灌注过程中形成了活性代谢物。
