Pharmacokinetics and metabolism of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol, a hypoglycemic agent, in man

Abstract

1. The pharmacokinetics and metabolism of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-[3-¹⁴C] indole-3-methanol, a new hypoglycemic agent, have been studied in 15 healthy male volunteers who received an oral dose of 50 or 200 mg.

2. The drug was rapidly and almost completely absorbed intact from the gastrointestinal tract.

3. Compared with the 50 mg dose, the 200 mg dose yielded less than proportionally higher blood concentrations of radioactivity and unchanged drug. This phenomenon has been observed previously in the rat and was probably due to an increase in drug distribution volume with increasing dose, since the metabolism and excretion patterns of the drug appeared to be dose-independent.

4. The drug was partially metabolized prior to excretion. Approximately 40% of the dose was recovered intact, almost exclusively in urine. The major metabolic pathway of the drug was by conjugation with glucuronic acid, while oxidation of the indole ring gave rise to a relatively minor metabolite.

5. The recovery of administered radioactivity was virtually complete within the experimental period, with a renal: faecal excretion ratio of ca 80: 20. The elimination half-life of unchanged drug was 25-30h while that of total radioactivity was 33-35 h.