Pharmacokinetic investigations in man of two acetyl derivatives of 16?-gitoxin

Abstract

3H-16-acetyl-16alpha-gitoxin or 3H-penta-acetyl-16alpha-gitoxin were injected iv or administered po to 15 volunteers and 3 patients. The elimination half-life and excretion in urine within 4 days were estimated as a percentage of the administered radioactivity, and metabolic studies on the fate of the administered glycosides were performed. In volunteers the following results were obtained: 3H-16-acetyl-16alpha-gitoxin 1 mg iv.: 50 +/- 11 h, 28.3 +/- 4.1%; 3H-16-acetyl-16alpha-gitoxin 1mg po: 48 +/- 8 h, 25.4 +/- 2.8%; 3H-penta-acetyl-16alpha-gitoxin 2 mg po: 51 +/- 12 h, 20.7 +/- 3.2%, respectively. In 3 patients with a cannulated bile duct 9.9% (mean) of the administered 3H-16-acetyl-16alpha-gitoxin was excreted. By comparison of the radioactivity excreted in urine following the 2 routes of 16-acetate administration, the percentage absorption was calculated to be 88.5%. In serum and urine 16-acetyl-16alpha-gitoxin and 16alpha-gitoxin were found as possible metabolites of both glycosides, in the ratio of 75-85:15-25, and both metabolites were also found in bile. Within 16 h after penta-acetate administration, two additional metabolites (bis-acetyl-derivatives of 16alpha-gitoxin) were detected in serum and urine within 16 h after administration of penta-acetate.

Studies on Cardioactive Steroids

“…This can be explained by differences in their elimina tion half-lives (t*/2). In healthy volunteers, t'/2 of the 16a-acetate [7] was 2.6 times longer than that of 16a-gitoxin (3,4).…”

“…In the isolated heart, 16a-gitoxin acetonide [4] was more effective than the unsubstituted glycoside [1:4 = 1.0:5.01, whereas acetonide formation of the 16a-acetate [8] slightly re duced the potency [7:8 = 10.0:0.711. The maximum inotropic effect (AItmax ) produced by both acetonides [4,8] was lower than that of the corresponding glycosides with free OH groups in the digitoxose moiety [1 ,7 ].…”

“…The maximum inotropic effect (AItmax ) produced by both acetonides [4,8] was lower than that of the corresponding glycosides with free OH groups in the digitoxose moiety [1 ,7 ]. Also helveticosol and its 3',4'-dinitrate had inotropic effects in an identical range of concentrations, whereas the extent of the inotropic effect was diminished by formation of the nitrate ester (10).…”