Distribution, elimination, metabolism and bioavailability of hexamethylenebisacetamide in rats

Summary

Hexamethylenebisacetamide (HMBA), an in vitro differentiating agent, was studied for its pharmaco-dynamic 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°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.