The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 ± 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 ± 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 ± 182 ml) and (+)PQ (930 ± 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life ((-)PQ 54 ± 29 min; (+)PQ 123 ± 33 min) and smaller area under the curve to infinity ((-)PQ254 ± 96μg ml-1.min, (+)PQ 387 ± 108 μg ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 ± 0.26 μg ml-1. min) than (+)PQ (0.19 ± 0.09 μg ml-1). There was no difference between the sum of the areas under the curve to 4hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 ± 64 μg ml-1 and 317 ± 75 μg ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 ± 0.02 ml min-1 and 0.14 ± 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites 0.24 ± 0.13 ml min-1 and 0.29 ± 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.