METABOLISM OF THE NEUROLEPTIC AGENT ZETIDOLINE IN THE RAT AND THE DOG

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (5) , 635-640
Abstract
The metabolism of zetidoline, a new neuroleptic, in the rat and the dog was studied. From the urine of rats and dogs given 5 mg/kg of [2-14C] zetidoline orally, unchanged drug and 5 metabolites were isolated and the structures of 4 of them assigned by physicochemical analysis. They are metabolite B, 4''-hydroxy-3''-chlorophenyl zetidoline; metabolite D, zetidoline without the aryl group; metabolite E, the 6''-hydroxy-4''-.beta.-D-glucuronide of metabolite B; and metabolite F, the 4''-.beta.-D-glucuronide of metabolite B. The plasma levels of zetidoline and its metabolites after i.v. administration show that the drug is rapidly excreted and/or metabolized in both animal species. The plasma radioactivity in the dog consists mainly of the pharmacologically active (neuroleptic) metabolite B, whereas in the rat it consists of the more polar metabolites. After oral administration, elimination in both species occurs mostly via the kidneys. In the dog, within a 24 h period, 6.2 .+-. 0.4% of the dose is accounted for as unchanged zetidoline, 7.6 .+-. 0.5% as metabolite B, 10.1 .+-. 0.7% as the unidentified metabolite C and 21.4 .+-. 1.1% as metabolite F. In the rat, over the same period, zetidoline is present in traces, metabolite B accounts for 6.9 .+-. 0.3% of the dose, metabolite D for 6.6 .+-. 0.9%, metabolite E for 15.2 .+-. 1.4% and metabolite F for 31.7 .+-. 2.2%.