TY - JOUR T1 - PHYSIOLOGICAL DISPOSITION AND METABOLISM OF TIMOLOL IN MAN AND LABORATORY ANIMALS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 361 LP - 370 VL - 3 IS - 5 AU - D. J. TOCCO AU - A. E. W. DUNCAN AU - F. A. DELUNA AU - H. B. HUCKER AU - V. F. GRUBER AU - W. J. A. VANDENHEUVEL Y1 - 1975/09/01 UR - http://dmd.aspetjournals.org/content/3/5/361.abstract N2 - Timolol [3-(3-tert.-butylamino-2-hydroxypropoxy)-4-morpholino-1,2,5-thiadiazole], was rapidly absorbed, metabolized, and effectively excreted in man, rats, and dogs. Peak plasma levels of timolol-14C were observed in these species 1-2 hr after oral administration. Generally, less than 20% of the radioactivity was present in the plasma in the unmetabolized form. The intact drug had a plasma half-life of 28 min in the rat, 48 min in the dog, and 5.5 hr in man. After oral administration of timolol-14C to humans approximately 72% of the dose was excreted in 84 hr, with 66% in the urine and 6% in the feces. In the rat, 58% of an oral dose was excreted in the urine and 26% in the feces. The dog excreted 68% of an oral dose in the urine and 19% in feces in 72 hr. Following intravenous administration, rats excreted 50% in the urine and 28% in the feces, which suggests that extensive biliary excretion occurred. Timolol was extensively metabolized. Approximately 50% of the radioactivity was identified in dog urine as the lactic acid metabolite. An additional metabolite was tentatively identified as the 3-oxomorpholino derivative of timolol. Approximately 20% of the dose in man was excreted in the urine unchanged. Two metabolites, resulting from cleavage of the morpholine ring, were identified as 1-tert-butylamino-3-[4-(2-hydroxyethyl-amino)-1,2,5-thiadiazol-3-yloxy]-2-propanol, accounting for 10% of the urine radioactivity, and 1-tert-butylamino-[4-(N-2-hydroxyethylglycolamido)-1,2,5-thiadiazol-3-yloxy]-2-propanol, accounting for 30%. A minor metabolite, resulting from hydroxylation of a terminal methyl group, accounted for an additional 3% of the urine radioactivity. Copyright © 1975 by The American Society for Pharmacology and Experimental Therapeutics ER -