Abstract
The metabolism of 1- [2-(4-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2-ol ('tolamolol'), a new beta-adrenoceptor blocking agent, has been studied in the mouse, rat, guinea pig, rabbit, dog and man. For these studies tolamolol was labelled with tritium and carbon-14. In all six species there was evidence for good absorption after oral administration, but the routes for excretion of radioactivity showed considerable variation between the species. The major route for excretion in mice, rats and guinea pigs was the faeces, but in rabbits and man the major route was the urine; the dog showed intermediate behaviour. Tolamolol was extensively metabolised, little unchanged drug being excreted. Two main metabolic pathways were identified. The most important pathway was hydroxylation of the 2-methylphenoxy ring, and this was the major biotransformation in all species except the dog. The second metabolic pathway, and the major route in the dog, was hydrolysis of the aromatic carbamoyl group. Significant hydrolysis also occurred in the rabbit but in other species this was a minor route. Glucuronide and sulphate conjugates of the hydroxylated metabolite were excreted in the urine of rabbits and man, and accounted for most of the excreted radioactivity in these two species. In the rat and guinea pig, and probably the mouse, conjugates were excreted in the bile rather than the urine, subsequently appearing in the faeces as the aglycones. The species difference in excretory routes is therefore due to differences in the extent of biliary excretion. A polar metabolite in dog urine has been tentatively identified as a sulphate ester, the aglycone being a secondary metabolite in which both aromatic hydroxylation and hydrolysis of the carbamoyl group have occurred. Cleavage of the alkyl chain did not occur to a significant extent in any of the species investigated.