Distribution, elimination, metabolism and bioavailability of hexamethylenebisacetamide in rats

• Published in: Investigational new drugs 1985-01, Vol.3 (3), p.263-272
• Main Authors: Litterst, C L, Roth, J S, Kelley, J A
• Format: Article
• Language: English
• Subjects: Acetamides - metabolism; Acetamides - urine; Animals; Biological Availability; Biotransformation; Chromatography, High Pressure Liquid; Kinetics; Male; Rats; Rats, Inbred Strains; Tissue Distribution
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/BF00179430

Hexamethylenebisacetamide (HMBA), an in vitro differentiating agent, was studied for its pharmacodynamic actions in animals. Plasma stability, organ distribution, excretion, oral bioavailability, and estimates of pharmacokinetic parameters and acute lethality were determined in rats. The single dose intraperitoneal LD50 was greater than 3000 mg/kg in both mice and rats. The drug was stable in plasma from several different species during an 8 h in vitro incubation at 37 degrees C. Following a single intravenous (iv) bolus injection (1000 mg/kg) to rats, HMBA was removed from the plasma with a half time of 2.2 +/- 0.5 h, and 65 +/- 8% of the dose was excreted unchanged in the urine during the first 24 h after dosing. During an 8 h iv infusion, plasma concentrations of 4 mM were easily maintained with no apparent adverse effects. Drug was uniformly distributed, with highest concentrations found in thymus, kidney, liver, and lymph node throughout the first 24 h after a single iv bolus dose. In vivo metabolism was very small, and the presence of apparent metabolites was undetectable until 48 h after iv administration. Oral bioavailability was good (32%), with peak plasma concentrations of 2 mM achieved one hour after oral administration. After oral dosing urinary excretion and plasma decay were comparable to similar data obtained after iv dosing.