The isolated perfused rat liver.

The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [C]mefloquine HCI (3.8 mg, 4 1 Ci, 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 T112 of 1.0 ± 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC0.. ) was 4.0 t 1.8 jug. hr , ml '. 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 quant~tated 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 ['C] dose was recovered from the livers. Subsequent HPLC analysis revealed this to be mostly unchanged mefloquine. Subeellular fractionation of the homogenized livers revealed that 50.6 ± 6.8% of the dose of mefloquine was located in the 10,000g pellet. In summary, mefloquine was cleared rapidly from the IPRL and underwent avid hepatic uptake into the lipid-rich fractions of rat liver. I Mefloquine (Fig/1) is a relatively new antimalarial position 4 of the quinoline ring was obtained under compound that is highly effective against chlorocontract to USAMRDC from the Chemistry and quine-resistant Plasmodiumfalciparum malaria. The Life Sciences Division, Research Triangle Institute, pharmacokinetics of mefloquine have been studied Research Triangle Park, NC. Radiochemical purity in dogs [1], rats [21 and humans [1, 3-6]. Mefloquine was determined by HPLC and TLC to be 99%. exhibits a large volume of distribution, is conNCS tissue solubilizer and hydrogen peroxide were centrated in soft tissues, is metabolized slowly, and supplied by Fisher Scientific (Fairlawn, NJ). Emulundergoes considerable biliary excretion in vivo sifying liquid scintillant "Aquasol" was obtained [1-3]. Mefloquine also inhibits hepatic metabolism from NEN Research Products, Boston, MA. All of aminopyrine in vitro in rat microsomes [7]. other reagents were of HPLC or analytical grade. Therefore, to investigate more fully the hepatic Animals. Male Sprague-Dawley rats ( 0 2 0g. handling of mefloquine, we have chosen the isolated Walter Reed Army Institute of Research Breeding perfused rnt liver (IPRL) preparation. This experColony) were housed in well ventilated cages and imental model excludes the influence of other organs kept at a room temperature of approximately 24'. and routes of elimination present in the intact animal They were allowed to feed ad lib. on pelleted food and has been of value in studies of the disposition of a number of compounds, e.g. cimetidine, propranolol, I 5 / w~e 1 4t suramin and the antimalarial primaquine [-11].(fe. ,4 it I /tA I MATERIALS AND METHODS HA Reagents. Mefloquine hydrochloride (WR A N C F, 142,490) and WR 184,806, the internal standard for CF, HPLC analysis, were both synthesized on contracts to the United States Army Medical Research and Development Command (USAMRDC) by Ash coos Stevens, Inc., Detroit, MI, and Starks Associates, Inc., Buffalo, NY, respectively. [1C]Mefloquine hydrochloride (sp. act. 10mCi/mmol) labeled at C N F, Author , huw ,ll orrespondence should be Fig. 1. Structural formulae of mefloquine (A) and its addressed. carboxy metabolite (B).