Identification of metabolites of [¹⁴C]zonampanel, an α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, following intravenous infusion in healthy volunteers

Abstract

This study determined the pharmacokinetics, metabolism and excretion of an a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist zonampanel monohydrate (YM872) after intravenous infusion of [14C]YM872 at 1 mg kg-1 h-1 for 2 h to four healthy male volunteers. Mean pharmacokinetic parameters of unchanged YM872 were 0.78 h for terminal half-life, 25.9 l h-1 for total clearance, 22.9 l h-1 for renal clearance, and 15.6 l for volume of distribution at steady-state. Urinary excretion of radioactivity accounted for 94.9% of the dose, and faecal excretion for only 0.5% of the dose. Measurement of YM872 concentrations by a high-performance liquid chromatography (HPLC)-ultraviolet method and radiometric HPLC metabolite profiling revealed that almost all of [14C]YM872 was excreted unchanged in the urine and that unchanged [14C]YM872 was the major circulating [14C] component in the plasma. Two minor metabolites, H1 and H2, detected in the urine and identified as the same chemical structures as those of the rat urinary metabolites, have a hydroxyamino group and an amino group, respectively, which were probably formed by reduction of the nitro group of YM872. These results show that virtually all of the administered YM872 remains unchanged, with urinary excretion representing the major elimination pathway. The high renal clearance implies tubular secretion of this drug.

Role of Organic Anion Transporters in the Pharmacokinetics of Zonampanel, an α-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonist, in Rats

“…Although zonampanel is metabolized only slightly in both rats and humans (Sohda et al, 2004;Minematsu et al, 2005), fecal excretion of […”

“…14 C]zonampanel to humans, urinary excretion of radioactivity and unchanged zonampanel accounted for 94.9 and 90.6% of the dose, respectively, whereas fecal excretion of radioactivity was only 0.5% (Minematsu et al, 2005 …”

“…1) is a selective antagonist of the glutamate receptor subtype, ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and has been accepted as a drug for the treatment of cerebrovascular disorders such as cerebral ischemia. Intravenous infusion of zonampanel has been shown to reduce the volume of ischemic damage in rats and cats .The major elimination route of zonampanel is renal excretion in humans (Minematsu et al, 2005). Potential mechanisms by which intravenously administered zonampanel is excreted unchanged into the urine in humans have been identified.…”

“…Potential mechanisms by which intravenously administered zonampanel is excreted unchanged into the urine in humans have been identified. The high renal clearance of this drug, approximately 30-fold greater than the product of the glomerular filtration rate (GFR) and the unbound fraction in plasma (f p ), suggests that renal tubular secretion contributes to excretion in the urine (Minematsu et al, 2005). Moreover, zonampanel, which exists as an anion under physiological conditions (pH ϳ7.0 -7.4), is transported by human organic anion transporter (OAT) 1 and OAT3, but not by OAT2 .…”

“…The major elimination route of zonampanel is renal excretion in humans (Minematsu et al, 2005). Potential mechanisms by which intravenously administered zonampanel is excreted unchanged into the urine in humans have been identified.…”