EXCRETION AND BIOTRANSFORMATION OF KETANSERIN AFTER ORAL AND INTRAVENOUS ADMINISTRATION IN RATS AND DOGS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (6) , 772-781
Abstract
The extraction and biotransformation of ketanserin, a novel serotonin S2-receptor blocking agent used in hypertension and related diseases, were studied after single p.o. [oral] (1 or 10 mg/kg) and i.v. (2.5 mg/kg) administration in rats and dogs, using 2 different radiolabels. Orally administered ketanserin was well absorbed and almost completely metabolized in both species. The excretion of the metabolites was rapid and amount to about 90% within 4 days. In the various groups of rats and dogs, excretion of the radioactivity with the feces (48 to 67%) exceeded that with urine (27 to 43%). In p.o. dosed bile-cannulated rats, 57% was excreted with the bile within 24 h, whereas about 30 to 40% of the biliary radioactivity was subjected to enterohepatic circulation. The major urinary, biliary and fecal metabolites were characterized by HPLC [high-performance liquid chromatography] and mass specrometric analysis. The main metabolic pathways of ketanserin were the aromatic hydroxylation at the quinazolinedione moiety, the oxidative N-dealkylation at the piperidine N, reduction of the ketone function and piperidine oxidation, followed by ring scission. The mass balance of the metabolites, as estimated by reversed-phase HPLC with one-line radioactivity detection, was very similar between male and female rats, as well as between rats p.o. dosed at 10 mg/kg and i.v. dosed at 2.5 mg/kg. In rats, major urinary metabolites resulted from the N-dealkylation pathway, whereas hydroxyketanserin was the main biliary and fecal metabolite. In dogs, the N-dealkylation pathway was less abundant, whereas higher doses resulted in smaller relative amounts of hydroxylated metabolites and larger relative amounts of ketanserin-oil, resulting from the ketone reduction. Dog plasma levels of ketanserin-ol exceeded those of the parent drug from about 5 h after p.o. dosing.