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Healthy volunteers administered orally a single dose (20 mg) of [2-14C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250-300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78 +/- 0.20 h. The simultaneous assay of plasma prolactin showed increased levels of the hormone (+ 464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B. The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7 +/- 1.7% in 4 days (73.4 +/- 1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3 [2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]-imidazolidin-2-one, metabolite D and the 4'-O-sulphate ester of metabolite B, metabolite G. The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.
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