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 (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms 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 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms 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.
Nicholl
D D
DD
Department of Pharmacology & Therapeutics, University of Liverpool, U.K.
Edwards
G
G
Ward
S A
SA
Orme
M L
ML
Breckenridge
A M
AM
D000818:Animals; D001646:Bile / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism*; D006207:Half-Life; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010477:Perfusion; D011319:Primaquine / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism
D002264:Carboxylic Acids; D011319:Primaquine