Disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3- methanol (59–801), a hypoglycaemic agent, in rats, dogs and monkeys

Abstract

1. The disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1 H-[3-¹⁴C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey.

2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60–75% in the monkey to 90% in the dog.

3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose.

4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1–7.2 h) and monkey (2.1–4.5 h).

5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1–2 days.