ACADESINE (AICA-RIBOSIDE) - DISPOSITION AND METABOLISM OF AN ADENOSINE-REGULATING AGENT

Acadesine (AICA-riboside) is a purine nucleoside analog with anti-isch emic properties that is currently being studied (Phase 3) for the prev ention of adverse cardiovascular outcomes in patients undergoing coron ary artery bypass graft (CABG) surgery. The safety, tolerance, and pha rmacokinetics of the drug hove previously been reported in this journa l (J Clin Pharmacol 1991;31:342-347). Recently, the authors studied th e disposition and metabolism of acadesine in healthy males (n = 4) aft er a 15-minute intravenous infusion of 25 mg/kg of 2-C-14-acadesine. T he postinfusion total C-14 concentrations in plasma declined in a mult iexponential manner, and the terminal phase had an apparent t1/2 of ab out 1 week. Intact acadesine was only measurable for 2 hours after inf usion. Total plasma clearance was 2.2 +/- 0.2 L/hour/kg, the acadesine blood/plasma ratio was unity, and plasma protein binding was negligib le (approximately 1%). Uric acid, the end product of purine metabolism in humans, was the major metabolite of acadesine in plasma and accoun ted for all of the total plasma C-14 at 6 hours after infusion. In who le blood, acadesine 5'-monophosphate was present in the red blood cell s, and the nucleotide represented 30% of the total blood C-14 at the e nd of the infusion. The nucleotide was confined to the RBCs and was no t present in plasma. Urine and fecal recoveries over 2 weeks accounted for 48% of the total C-14 dose, with 44% excreted in urine and 4% in feces. Only 5% of the dose was excreted in urine as intact acadesine. Uric acid was the major metabolite in urine together with small amount s of hypoxanthine. There was no evidence of conjugation of acadesine o r its metabolites with glucuronic acid. Our study indicates that acade sine is metabolized to uric acid through normal purine pathways. Acade sine metabolites also enter the endogenous purine pools and are distri buted throughout the body.