Metabolism, tissue distribution and covalent binding of tripelennamine and its N-nitroso derivative in the rat

GS Rao, G Krishna and JR Gillette

Benzyl-14C-labeled tripelennamine and its N-nitroso derivative (NDT) were administered (20 mg/kg; 50 muc/kg i.p.) separately to control and phenobarbital-pretreated rats. Tissue distribution and covalent binding of the two compounds in liver, lung, kidney, fat and muscle tissues, as well as in the plasma, were determined at 4 and 24 hours after the administration. No specific localization of the test compounds to any tissue or to the plasma was observed. The in vivo covalent binding of both the compounds to the proteins of the tissues and plasma was low; the highest binding occurred in the liver (approximately 25 pmol/mg of protein). Within 24 hours about 78% of the injected tripelennamine and its metabolites was excreted into the urine whereas only about 35% of the radioactivity of NDT was eliminated. Pretreatment with phenobarbital accelerated the elimination of both substances. The metabolites of the drug and NDT were isolated from urine, hydrolyzed by glucuronidase-sulfatase and identified as their trimethylsilyl derivatives by gas chromatography-mass spectrometry. Tripelennamine was found to be extensively metabolized by N-demethylation and aromatic hydroxylation pathways. By contrast most of the NDT was eliminated as NDT and hydroxylated metabolites; very little was excreted as N- demethylated metabolites. The hydroxylated metabolites identified were p-hydroxybenzyl, p-hydroxybenzyl-5-hydroxypyridyl and m,p- dihydroxybenzyl derivatives of the drug, its N-demethylated analog and NDT. The catechol formation with NDT was found to be 4 times that observed with tripelennamine.

Volume 195, Issue 3, pp. 433-440, 12/01/1975
Copyright © 1975 by American Society for Pharmacology and Experimental Therapeutics

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