THE DISPOSITION OF AN ANTILEISHMANIAL 8-AMINOQUINOLINE DRUG IN THE ISOLATED PERFUSED-RAT-LIVER - THERMOSPRAY LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY IDENTIFICATION OF METABOLITES

1. The disposition of the candidate antileishmanial drug 8-(diethylaminohexylamino-6-methoxy-4-methyl quinoline dihydrochloride (I) has been investigated in the isolated perfused rat liver preparation after the administration of 5 mg/kg (25 μCi) of 14C-I. 2. The perfusate concentration of unchanged I declined biexponentially over the 4 h study period, with a distribution i1/2 of 3.3±0.3min and a terminal t1/2 of 35.4±13.6min. The area under the perfusate plasma concentration/time curve (AUCo.last time point) was 53.3 ± 15.7 μ min/ml, representing 96% of the area under the curve extrapolated to infinity. The perfusate contained predominantly the carboxylic acid metabolite of I, as well as trace quantities of metabolites detected and identified in bile. 3. Biliary excretion of total 14C accounted for 18.2 ± 5.0% of the dose, only 2.8 ± 0.7% was identified by h.p.l.c. analysis as unchanged I. The remainder of the bile contained the desethyl metabolite of I as well as a minimum of 12 more polar metabolites. After 4 h, a total of 39.0 ± 8.3% of dosed 14C was recovered from the liver tissue. Subcellular fractionation of the livers revealed 24.6 ± 2.2% of 14C to be located in the 10000 g pellet. 4. Thermospray liquid chromatography - mass spectrometry analysis of untreated bile and bile treated with glucuronidase or aryl sulphatase permitted identification of some of these metabolites, revealing the presence of the parent drug, desethyl metabolite, 6-desmethyl glucuronide, the 6-desmethyl desethyl glucuronide and the side-chain cleaved 8-amino N-glucuronide metabolites of I, as well as the 6-desmethyl sulphate and the 6-desmethyl desethyl sulphate. Two dihydroxylated metabolites were also detected; however, further structure elucidation is required for unambiguous identification. © 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.