Species differences in the urinary excretion of the novel primary amine conjugate: tocainide carbamoyl O-beta-D-glucuronide.
The metabolism of the antiarrhythmic drug tocainide (I) has been shown previously to occur via a novel pathway involving the addition of carbon dioxide to the primary amine nitrogen of I followed by conjugation with glucuronic acid. The product of this reaction, tocainide carbamoyl O-beta-D-glucuronide (II), the principal metabolite of I in humans, has been found to cyclize under strongly basic conditions to form 3-(2,6-xylyl)-5-methylhydantoin (III). Thus, evidence for the existence of II can be obtained by two different procedures: conversion of II to III in the presence of strong base and by hydrolysis of II with beta-glucuronidase. The principal purpose of the present investigation was to identify suitable species for studies of the mechanism involved in the formation of II, as well as to find an animal model suitable for toxicological evaluation of tocainide and structurally related compounds. Eight animal species were examined to identify those capable of metabolizing I into II. The fraction of an intraperitoneal dose excreted in urine as II was estimated by measurement of tocainide released by beta-glucuronidase mediated hydrolysis of urine and by the quantitation of III formed after alkalinization of urine samples. Urinary recovery of unchanged drug ranged from 9.5% of the dose in the gerbil to 48.7% in the cat. The percent of the dose excreted in urine as acid hydrolyzable conjugates ranged from less than 1% in the gerbil to a mean of 13% in the rabbit. Guinea pigs, dogs, cats, rabbits, and pigtail monkeys excreted amounts of II ranging from 0.2 to 2.4% of the dose. Thus, none of the species appeared to be a suitable model for the study of the mechanism of formation of II because of the quantitative insignificance of this pathway.
D000818:Animals; D002415:Cats; D002522:Chlorocebus aethiops; D004285:Dogs; D005849:Gerbillinae; D006168:Guinea Pigs; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000652:urine; D008254:Macaca nemestrina; D051379:Mice; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D016677:Tocainide / Q000031:analogs & derivatives*
D016677:Tocainide; C033805:tocainide carbamoyl O-beta-glucuronide; D008012:Lidocaine