TIMOLOL METABOLISM IN MAN AND LABORATORY-ANIMALS

  • 1 January 1980
    • journal article
    • research article
    • Vol. 8  (4) , 236-240
Abstract
The 2 major urinary metabolites of the .beta.-adrenergic blocking agent and antiglaucoma drug 14C-timolol in man, involving oxidation and hydrolytic cleavage of the morpholine ring, are observed in both Sprague-Dawley rats and CRCD-1 mice. These are the N-[[4-[3-(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,5-thiadiazol-3-yl]-N-(2-hydroxyethyl)glycine and 1-(1,1-dimethylethylamino)-3-{[4-(2-hydroxyethylamino)-1,2,5-thiadiazol-3-yl]oxy}-2-propanol. The former was previously identified erroneously as the isomeric compound 1-(1,1-dimethylethylamino)-3-{[4-(N-2-hydroxyethylglycolamido)-1,2,5-thiadiazol-3-yl]oxy}-2-propanol. Rats and mice had 2 additional metabolites in common, 1-[(1,1-dimethylethyl)amino]-3-{[4-(2-hydroxy-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy}-2-propanol and a compound now proposed to be the corresponding morpholino lactone 1-[(1,1-dimethylethyl)-amino]-3-{[4-(2-oxo-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy}-2-propanol but for which the corresponding isomeric morpholino lactam structure 1-[(1,1-dimethylethyl)-amino]-3-{[4-(3-oxo-4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy}-2-propanol was tentatively proposed in an earlier publication. A metabolite observed in the rat, but not in the other species studied, was 4-(4-morpholinyl)-1,2,5-thiadiazol-3-ol-1-oxide. The metabolic pattern in these rodents does not change significantly after repeated doses. A scheme summarizing the metabolic fate of timolol in man and laboratory animals is presented.