Acadesine
Acadesine, a nucleoside. A cell-permeable adenosine analogue phosphorylated intracellularly to ZMP, which allosterically mimics AMP at… Oral half-life 1.4 h.
A cell-permeable adenosine analogue phosphorylated intracellularly to ZMP, which allosterically mimics AMP at AMP-activated protein kinase — so it activates AMPK without perturbing the cell's own adenine nucleotide pool. PMID:7744080 verbatim: "ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP." That assay is rat hepatocytes and adipocytes. NO AFFINITY CONSTANT IS AUTHORED AND NONE WOULD BE THE RIGHT PRIMITIVE: the target engagement is intracellular and allosteric, so a Hill occupancy row against a plasma curve would misrepresent it. Prohibited in sport as an AMPK-activating metabolic modulator.
THE R15 VOLUME DERIVATION IS NOW CORROBORATED BY AN INDEPENDENT STUDY, which is why this batch went to full text. PMC3579463 (PMID:23228986), a phase I in CLL, publishes the table the abstract omits: at the 210 mg/kg optimal biological dose the median AUC(0-24) is 123,125 ng.h/mL. At the 70 kg reference that dose is 14,700 mg, so CL = 14,700 mg / 123.125 mg.h/L = 119 L/h. THE STORED DERIVATION IMPLIES 175 L/h and the verbatim Vss of 112 L would have implied 55 L/h: the derived figure lands within 1.5x of an independent patient study while the verbatim one is off by 2.2x in the other direction. THE CLL HALF-LIVES ARE NOT PORTABLE: the same table gives medians from 3.9 to 61.4 h with within-cohort spreads of 2.6 to 106 h, against 1.4 h in healthy men, so nothing here displaces the stored values. REGISTERED UNDER `acadesine`, NOT `AICAR`, AND THE REASON IS A 31% MASS ERROR. PubChem `acadesine` returns CID 17513 (C9H14N4O5, 258.23) — the riboside, which is the administered drug and the molecule the AMPK literature calls AICAR. PubChem `AICAR` returns CID 65110 (C9H15N4O8P, 338.21), which the phosphate in the formula gives away: that is ZMP, the intracellular MONOPHOSPHATE metabolite. Both re-queried 2026-09-26. An unqualified `AICAR` lookup therefore yields a mass 31% too high for a phosphorylated species the patient is never given, so the alias points here rather than the reverse. No salt form; free nucleoside in both PK studies. DOSES are a declared conversion from mg/kg at the 70 kg reference: 10-100 mg/kg in the healthy-volunteer study (PMID:2037706) gives 700-7000 mg, the 25 mg/kg of both PK studies gives the stored typical 1750 mg, and the CLL trial's ceiling, "210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD)" (PMID:23228986), gives 14700 mg. THE HALF-LIFE THAT MUST NEVER BE STORED IS ONE WEEK. PMID:8227467 reports "the terminal phase had an apparent t1/2 of about 1 week" — but that is TOTAL 14C, dominated by the metabolite, and the same abstract says "Intact acadesine was only measurable for 2 hours after infusion" and "Uric acid ... was the major metabolite of acadesine in plasma and accounted for all of the total, plasma 14C at 6 hours". Storing 168 h against the parent's 1.4 h would be a 120-fold analyte error, worse than the carisoprodol case R10 cites. That abstract is also TRUNCATED at 250 words, so anything not quoted from it is not retrieved rather than absent. HUMAN USE IS NOT LIMITED TO CARDIAC SURGERY: healthy-volunteer IV and oral PK (PMID:2037706, PMID:8227467), healthy-volunteer AMPK physiology in 29 men (PMID:17513706, which states no dose), CABG phase 3, and relapsed CLL (PMID:23228986). A MECHANISM CLAIM NOT TO ADOPT: a 2008 development profile opens "Acadesine is an adenosine receptor agonist", which conflicts with the primary AMPK literature; no adenosine-receptor affinity is authored off it. Dose-independence is certified by the source: "there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose."
Pharmacokinetics
- IV — t½ 1.4 h · F 100% · Vd 353.5 L
- Oral — t½ 1.4 h · F 5% · Vd 353.5 L
Sources: PMID:2037706, PMID:8227467, PMID:2813961, PMID:7744080, PMID:23228986, PMID:17513706