RT Journal Article
SR Electronic
T1 Timolol metabolism in man and laboratory anamals.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 236
OP 240
VO 8
IS 4
A1 Tocco, D J
A1 Duncan, A E
A1 deLuna, F A
A1 Smith, J L
A1 Walker, R W
A1 Vandenheuvel, W J
YR 1980
UL http://dmd.aspetjournals.org/content/8/4/236.abstract
AB The two major urinary metabolites of 14C-timolol in man, involving oxidation and hydrolytic cleavage of the morpholine ring, are also observed in both Sprague-Dawley rats and CRCD-1 mice. These are the N-T(4-[3-(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,5-thiadiazol-3-ylT-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 two 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-dimethylenthyl)-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.