Coleman M D, Fleckenstein L, Shipley L A, Heiffer M H
Department of Pharmacology, Walter Reed Army Medical Center, Washington, DC 20307-5100.
Biochem Pharmacol. 1988 Jan 15;37(2):235-9. doi: 10.1016/0006-2952(88)90723-x.
The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [14C]mefloquine HCl (3.8 mg, 4 microCi, quinoline ring labeled). Mefloquine underwent avid hepatic uptake within 10 min of dosing. Also at this point, hepatic oxygen consumption was reduced markedly in four of the six IPRL preparations, but was restored completely by approximately 30 min post-dose. The drug concentration profile underwent a biexponential decline over the 4-hr study period, with a terminal T1/2 of 1.0 +/- 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC0-infinity) was 4.0 +/- 1.8 micrograms.hr.ml-1. Mefloquine was a high clearance compound (956.0 +/- 390 ml/hr) with a large apparent volume of distribution (1416 +/- 819 ml) in the IPRL. Biliary excretion accounted for 7.5 +/- 6.5% of the dose. Mefloquine was quantitated by HPLC analysis as approximately half (3.3 +/- 1.8%) of biliary label, the remainder consisting of highly polar metabolites of mefloquine. By 4 hr, a total of 64.8 +/- 4.4% of the [14C] dose was recovered from the livers. Subsequent HPLC analysis revealed this to be mostly unchanged mefloquine. Subcellular fractionation of the homogenized livers revealed that 50.6 +/- 6.8% of the dose of mefloquine was located in the 10,000 g pellet. In summary, mefloquine was cleared rapidly from the IPRL and underwent avid hepatic uptake into the lipid-rich fractions of rat liver.
在给予[14C]盐酸甲氟喹（3.8毫克，4微居里，喹啉环标记）后，在离体灌注大鼠肝脏（IPRL）制备物中研究了甲氟喹的处置情况。给药后10分钟内，甲氟喹迅速被肝脏摄取。此时，在六个IPRL制备物中的四个中，肝脏耗氧量显著降低，但在给药后约30分钟完全恢复。在4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1.0±0.3小时。灌注液血浆浓度/时间曲线下面积（AUC0-∞）为4.0±1.8微克·小时·毫升-1。甲氟喹是一种高清除率化合物（956.0±390毫升/小时），在IPRL中的表观分布容积较大（1416±819毫升）。胆汁排泄占给药剂量的7.5±6.5%。通过HPLC分析定量，胆汁标记物中甲氟喹约占一半（3.3±1.8%），其余为甲氟喹的高极性代谢物。到4小时时，从肝脏中回收了[14C]剂量的64.8±4.4%。随后的HPLC分析表明，这主要是未变化的甲氟喹。对匀浆肝脏进行亚细胞分级分离显示，甲氟喹剂量的50.6±6.8%位于10000g沉淀中。总之，甲氟喹从IPRL中迅速清除，并被大鼠肝脏富含脂质的部分迅速摄取。
