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

Abstract

Thymoxamine, a prodrug, is rapidly deacetylated in the plasma to give two phase I metabolites, DMAT and DAT, which are further sulpho- and glucuro-conjugated and then excreted mainly in the urine. In a cross-over study, the dose-dependence of the metabolite ratio was evaluated in nine healthy volunteers after three doses (120, 240, 480 mg) of thymoxamine-HCl. Regardless of the dose, DMAT and its glucuronide were not detected, while the amount of DMAT-sulphate was found to be proportional to the dose administered. Plasma levels of DAT were measurable in only four of the nine subjects after the 480 mg dose and showed great intersubject variability. The pharmacokinetics of both DAT-sulphate and DAT-glucuronide were dose-dependent. As the dose increased, the proportion of DAT undergoing sulphatation decreased; this saturation was compensated by glucuronidation.

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

“…With regard to the conjugates, in the above-mentioned study in two subjects [43], 45% and 47% of the dose were ascribed to DAM-S after intravenous and oral administration respectively, 11% and 15% to MDAM-S and 37% and 28% to DAM-G. However, patterns reported elsewhere after oral [25] and after intravenous [ 151 administration were quite different. Based on AUC, the conjugates ranked DAM-G > DAM-S > MDAM-S in the oral experiment, while in the iv, DAM-S and MDAM-S were equivalent and twice as high as DAM-G. No difference in metabolite formation was shown to occur between intravenous and intracavernous administration.…”

“…Based on the T,,, values of the conjugates, absorption of moxisylyte was shown to be not saturable up to 480 mg [25].…”

Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses

“…Moxisylyte (thymoxamine, 4-(2-dimethylamino-ethoxy)-5-isopropyl-2-methyl phenyl acetate), an ~-adrenoceptor predominate blocking agent [3], is the first drug with marketing authorisation in France for the treatment of impotence [4][5][6]. Its pharmacokinetics has been studied after IV [7][8][9], IC [8,10], and oral administration [7,11,12]. Moxisylyte can be considered as a prodrug, since rapid biotransformation occurs in blood.…”