Metabolism of¹⁴C-thymoxamine in rat and man

Abstract

1. After oral administration of 14C-thymoxamine to rat and man the total 14C excreted in urine and faeces was determined. 2. Six metabolites were isolated from the excret of man and rat by chemical extraction and identified by g.l.c.-mass spectral analyses. 3. Two other metabolites, highly polar and resistant to enzymic hydrolysis, were isolated by extraction on XAD2 resin and h.p.l.c. analysis. These two metabolites were identified by n.m.r. and by mass spectrometry in the fast atomic bombardment mode. 4. These two major metabolites of thymoxamine in man and rat have been identified and characterized as the sulphate conjugates of desacetyl-thymoxamine and N-monodesmethyl-desacetyl-thymoxamine.

Moxisylyte: A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in impotence

“…In vitro experiments from Nielsen-Kudsk showed that its half-life in plasma was about 1 min and that cholinesterase was the enzyme responsible DAM is mainly eliminated by metabolic transformation in the liver; either by N-demethylation into MDAM, sulphoconjugation into DAM-S or glucuroconjugation giving rise to DAM-G [43, 441. Elimination of MDAM has been shown to occur mainly by sulphoconjugation in man. The glucuronide of MDAM (MDAM-G) accounted for only 1 % of the dose in urine of subjects given an oral dose of 60 mg [17] and was not detected in plasma at higher doses As with MDAM-G, unconjugated MDAM was not found in plasma whatever the route of administration, (oral, intravenous or intracavernous [ 15,251. However, it was found in trace amounts in urine of volunteers [ 171.…”

Multiple-Dose Pharmacokinetics of Moxisylyte after Oral Administration to Healthy Volunteers

“…During the metabolism studies, enzymatic hydrolysis with either the juice of Helixpomatiu or p-glucuronidase or arylsulfatase did not result in the complete cleavage of the coqjugated metabolites.18 Indeed, 65% of glucuronides are not hydrolyzed by p-glucuronidase from bovine liver; sulfate conjugates are not hydrolyzed by either sulfatase or H. pomatia juice.18 In our experience, after hydrolysis with the juice of H. pomatiu, -44% of conjugated derivatives are not cleaved. 17 The use of a selective acid hydrolysis to separate the sulfate from the glucuronide conjugates was not possible. Despite the findings of Hengy et al.19 showing that the yield of sulfate hydrolysis was 87-95% and the glucuronide hydrolysis was 5% (1 M HC1,2 h, 80 "C) under the same experimental conditions, our results indicated an incomplete (-80%) and variable hydrolysis of sulfate and a partial hydrolysis (5-20%) of glucuronide.…”

Pharmacokinetics of a prodrug thymoxamine: Dose-dependence of the metabolite ratio in healthy subjects

“…and are then excreted mainly in the urine (1(}-12). Of the total urinary elimination in man, 1% is represented by 4-hydroxy 5-isopropyl-2-methyl phenol in equilibrium with thymoquinone (7).…”