Acadesine (AICA‐Riboside): Disposition and Metabolism of an Adenosine‐Regulating Agent

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Abstract
Acadesine (AICA‐riboside) is a purine nucleoside analog with anti‐ischemic properties that is currently being studied (Phase 3) for the prevention of adverse cardiovascular outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. The safety, tolerance, and pharmacokinetics of the drug have previously been reported in this journal (J Clin Pharmacol 1991;31:342–347). Recently, the authors studied the disposition and metabolism of acadesine in healthy males (n = 4) after a 15‐minute intravenous infusion of 25 mg/kg of 2‐14C‐acadesine. The postinfusion total 14C concentrations in plasma declined in a multiexponential manner, and the terminal phase had an apparent t1/2 of about 1 week. Intact acadesine was only measurable for 2 hours after infusion. Total plasma clearance was 2.2 ± 0.2 L/hour/kg, the acadesine blood/plasma ratio was unity, and plasma protein binding was negligible (∼1%). Uric acid, the end product of purine metabolism in humans, was the major metabolite of acadesine in plasma and accounted for all of the total plasma 14C at 6 hours after infusion. In whole blood, acadesine 5′‐monophosphate was present in the red blood cells, and the nucleotide represented 30% of the total blood 14C at the end of the infusion. The nucleotide was confined to the RBCs and was not present in plasma. Urine and fecal recoveries over 2 weeks accounted for 48% of the total 14C 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 amounts of hypoxanthine. There was no evidence of conjugation of acadesine or its metabolites with glucuronic acid. Our study indicates that acadesine is metabolized to uric acid through normal purine pathways. Acadesine metabolites also enter the endogenous purine pools and are distributed throughout the body.