Metabolism of isometheptene in human urine and analysis by gas chromatography-mass spectrometry in doping control.

A study of the metabolism of isometheptene, an antispasmodic drug, in man and comparison with heptaminol metabolism, is presented in this paper. Isometheptene and two metabolites were detected in human urine after oral administration of a tablet containing isometheptene mucate. The urine level of the parent drug, which is excreted during the first 24 h, was determined using gas chromatography-mass spectrometry, after alkaline extraction with organic solvent. A minor metabolite of isometheptene was converted to heptaminol in vitro under the acidic hydrolysis conditions used for the screening procedure of stimulants and narcotics in doping control analysis.

[Heptaminol chlorhydrate: new data]. / Le chlorhydrate d'heptaminol: nouvelles données.

Heptaminol hydrochloride is widely used for the treatment for orthostatic hypotension. It continues to elicit controversy as to its mode of action since Loubatières (1951) described its powerful inotropic action on an ischaemic preparation. Twenty five years later it has been suggested that this drug exerts its action by interfering with the release and uptake of catecholamines (Grobecker and Grobecker, 1976). The aim of this review was to report new experimental approaches and new data relative to the mode of action of heptaminol hydrochloride. In the rat, heptaminol hydrochloride prevented orthostatic hypotension, and increased the noradrenaline plasma concentration. In bovine chromaffin cells maintained in primary cultures, it was found to be a competitive inhibitor of noradrenaline uptake. This inhibition may partially account for its antihypotensive effect. The cardiotonic effect was studied using 31 P nuclear magnetic resonance spectroscopy and left ventricular pressure measurement in rat isolated hearts. The results suggest that the inotropic effect during moderate ischemia could be related to a restoration of internal pH possibly mediated by a stimulation of the Na+/H+ exchange. The satellite cells of adult skeletal muscles are myogenic cells involved in muscle regeneration. In culture, they differentiate into myotubes and thus mimic some aspects of the in vivo myogenic process. Heptaminol hydrochloride, which did not significantly alter the cloning efficiency or proliferation, increased the capacity of satellite cells to differentiate into myotubes.

Absorption, distribution, elimination and metabolism of 14C-heptaminol hydrochloride in rat.

Absorption, distribution, excretion and metabolism studies with 14C-labelled 6-amino-2-methyl-2-heptanol hydrochloride (14C-heptaminol hydrochloride, Hept-amyl) were carried out in rat. After a 10 mg/kg p.o. dose heptaminol was rapidly and entirely absorbed. Following the administration of 8 mg/kg i.v. or 12 mg/kg p.o., all tissues studied, except brain, contained higher levels of radioactivity than did plasma. No evidence of accumulation of the drug was seen in any tissue. Whole-body autoradiography revealed a preferential localisation in salivary glands, hypophysis and adrenal medulla 1 h after a 10 mg/kg i.v. or p.o. dose. Brain autoradiography showed radioactivity localised only in highly vascularised areas (choroid plexus and pia mater). Excretion occurred mainly by kidney, 68% of the radioactivity being excreted in urine 4 h after a dose of 10 mg/kg i.v. Biliary and faecal elimination accounted for less than 1% of the radioactivity administered. Heptaminol was metabolized to a hydroxylated metabolite, 6-amino-2-methyl-1,2-heptanediol, which was excreted unconjugated in urine. As doses increased from 10 to 200 mg/kg p.o., the amount of metabolite excreted in the 24-h urines decreased from 7.05% to 4.24% of the urinary radioactivity, indicating a saturation of the metabolism at high doses. Pretreatment of rats with phenobarbital increased the percentage of metabolite excreted in urine, but was unable to prevent the saturation of the metabolism at high doses of heptaminol.