Metabolism, kinetics and metabolic activity of the beta-cytotropic antidiabetic 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium (glydanile sodium) in man after oral and intravenous administration

Abstract

The metabolism and pharmacokinetics of [3H]-labelled 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium ([3H]-glydanile sodium) were investigated in three diabetics and six healthy volunteers after oral and i.v. administration. In the healthy volunteers the level of compound in plasma was correlated to insulin concentration and free fatty acids in plasma or serum, both after oral and i.v. administration of glydanile sodium. After oral administration of 10 mg I13H]-glydanile sodium, maximum [3H] concentration in plasma is found after 2--4 h. The concentration corresponds to 60-90 mug/100 ml when calculated as mug glydanile sodium in plasma. Glydanile is metabolized rapidly. The four metabolites which have been isolated and identified represent more than 95% of total radioactivity in urine. The main metabolite occurring in plasma and urine is the tertiary isobutyl alcohol of glydanile (metabolite I). This metabolite still possesses about 30% of the hypoglycaemic activity of the original compound. The initial half-life of unchanged glydanile after i.v. injection is about 30-40 min. In human plasma more than 99% of the glydanile present is in the protein-bound form. After oral administration, about 20% of radioactivity is eliminated with urine and about 80% with faeces. After i.v. injection, about 70% of radioactivity is eliminated with urine and about 30% with faeces. After oral administration, only about 30% of the compound given was absorbed under these experimental conditions. It may be possible to improve the poor absorption demonstrated in these trials by making the drug available in another, suitable, oral dosage form. Glydanile is eliminated rapidly via urine and faeces after oral and i.v. administration, which means that no accumulation, involving the danger of hypoglycaemic reactions, need be expected. Plasma insulin is increased by a glydanile concentration of 10-20 mug/100 ml plasma.