The effect of the monoamine oxidase inhibitor isocarboxazid on the canine metabolism of the cell-differentiating agent hexamethylene bisacetamide

Abstract

The acute toxicities of the cellular differentiating agent hexamethylene bisacetamide (HMBA) in humans and animals include CNS toxicity (agitation, somnolence, seizures, hallucinations) and an anion-gap metabolic acidosis. N-Acetyl-1,6-diaminohexane (NADAH), the first metabolite of HMBA, is as active as the parent compound in causing differentiation of leukemic cells in vitro, whereas 6-acetamidohexanoic acid (6AcHA), which is formed by the oxidation of NADAH in the presence of monoamine oxidase (MAO) and aldehyde dehydrogenase, is inactive. To test whether the inhibition of MAO blocks the production of an inactive and possibly toxic HMBA metabolite (6AcHA) or increases the amount of active compounds (HMBA + NADAH) in vivo, we investigated the effect of the MAO inhibitor isocarboxazid on the metabolism and toxicity of HMBA in beagle dogs. Two groups of dogs, composed of one male and one female dog per group, were used in the study. One group received isocarboxazid (3.3 mg/kg p.o. q8h x 9) beginning at 24 h before the initiation of a 48-h i.v. infusion of HMBA (40 mg kg-1 h-1), whereas the other received placebo in an identical fashion prior to the start of an identical HMBA infusion. The mean plasma steady-state concentration (css) of HMBA was 0.91 mM in dogs given HMBA and isocarboxazid as opposed to 0.78 mM in those given HMBA and placebo. As measured spectrophotometrically, plasma MAO activity was inhibited by 86% +/- 3% in dogs receiving isocarboxazid. Gas chromatography/mass spectrometry detected 6AcHA in the plasma of animals that were given placebo but not in the plasma of dogs that received isocarboxazid. Gas chromatographic analysis of urine samples revealed that the total amount of 6AcHA and of NADAH excreted in urine was 8 times less and 3 times greater, respectively, in isocarboxazid-treated dogs than in animals that received HMBA and placebo. One dog was excitable after the initial two doses of isocarboxazid and developed seizures at the end of the HMBA infusion. Another dog was agitated during treatment with HMBA and isocarboxazid. No CNS toxicity occurred in animals that were treated with HMBA and placebo. We conclude that isocarboxazid inhibits the production of 6AcHA in vivo, thus supporting the involvement of MAO in HMBA metabolism. Because the combination of HMBA and isocarboxazid produces CNS toxicity, 6AcHA is probably not the neurotoxic agent in dogs.