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AICA‐Riboside: Safety, Tolerance, and Pharmacokinetics of a Novel Adenosine‐Regulating Agent
Author(s) -
Dixon Ross,
Gourzis James,
McDermott Daniel,
Fujitaki James,
Dewland Peter,
Gruber Harry
Publication year - 1991
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1991.tb03715.x
Subject(s) - pharmacokinetics , riboside , pharmacology , placebo , medicine , volume of distribution , adenosine , oral administration , chemistry , endocrinology , biochemistry , alternative medicine , pathology
AICA‐riboside (5‐amino‐4‐imidazole carboxamide ribonucleoside) is a novel adenosine‐regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo‐controlled, double‐blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1‐week wash‐out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post‐infusion plasma concentrations of AICA‐riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t t/2 β of 1.4 hours. Total plasma clearance (CL), mean residence time (MRT IV ), and volume of distribution at steady‐state (V SS ) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5′‐monophosphate nucleotide. Renal clearance (CL R ) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA‐riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences ( P > .05) in the mean estimates of t 1/2 β, CL, CL R , MRT IV and V SS associated with dose. The drug was poorly bioavailable (<5%) when administered orally in solution.