The pharmacokinetics and metabolism of idazoxan in the rat

Abstract

1. [2'-14C]Idazoxan was rapidly and completely absorbed after its oral administration to rats. 2. After administration of either [2'-14C] or [6,7-3H]idazoxan, radioactivity was taken up by a wide range of tissues and became localized, especially in the organs of metabolism and excretion. Quantitative distribution patterns were route-dependent such that oral dosing resulted in lower radioactivity concentrations in all tissues apart from liver. 3. Clearance of idazoxan (94-144 ml/min per kg) was due mostly to metabolism and was independent of dose. Oral bioavailability in male rats at low oral doses of idazoxan (10 mg/kg) was about 1%, but increased with increasing dose to 23% at 100 mg/kg. Oral bioavailability in female rats was considerably higher than in male rats, at all doses studied. Brain idazoxan levels were in equilibrium with those in plasma, but ten-fold higher. 4. Elimination of radioactivity after administration of 14C-idazoxan was via the urine and the faeces (about 75% and 20% of dose respectively) and occurred essentially in the 24 h period immediately after dosing. By 96 h after dosing, elimination was virtually complete, with less than 0.5% dose remaining in the carcasses. 5. Biotransformation was by hydroxylation at positions 6 and 7 to form phenolic metabolites, which were excreted as glucuronide and sulphate metabolites in urine, but unconjugated in faeces. Other minor metabolic routes were 5-hydroxylation or oxidative degradation of the imidazoline ring, but these pathways were of quantitatively minor importance in the rat.

Neural mechanisms underlying peak‐dose dyskinesia induced by levodopa and apomorphine are distinct: Evidence from the effects of the alpha2 adrenoceptor antagonist idazoxan

“…At this, or later times, idazoxan has no effect on apomorphine‐induced dyskinesia. Furthermore, the dosing regime, i.e., administration of idazoxan at the same time as levodopa or apomorphine, was based on pharmacokinetic studies of idazoxan in rodents (there are no published data on the pharmacokinetics of idazoxan in marmoset), which suggest that orally administered idazoxan is rapidly absorbed, reaching effective plasma concentrations within 10–15 minutes 27…”

Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

“…Rush et al showed that this metabolite (their RM7) had the oxygen on position 6 and/or 7 by comparison to an authentic standard. A similar result was obtained for the related idazoxan [15]. M3 had two exchangeable hydrogens.…”

The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water intake in the rat

“…This could be due to metabolism of the compounds in vivo (for example, idazoxan has a half-life in plasma of about 1 h; Lewis et al, 1988) and/or reflect compensatory satiation following the initial feeding and drinking bouts (water intakes of animals treated with high doses of the x2-antagonists tended to be lower than controls in the 20 h period between the 4 and 24h readings, and, food intake was significantly decreased in this interval by the highest dose of idazoxan). Interestingly, L-659,066, at a high dose, significantly decreased body weight over 24 h. The reasons for this decrease, which were not observed for the other compounds, are unclear.…”