Disposition of the antimalarial, mefloquine, in the isolated perfused rat liver

Abstract

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 μCi, 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 T 1 2 of 1.0 ± 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC 0-∞) was 4.0 ± 1.8 μg·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.