Glucuronidation of digitalis glycosides by rat liver microsomes: stimulation by spironolactone and pregnenolone-16 alpha-carbonitrile

In the present studies, glucuronidation of [ 3 H]digoxigenin monodigitoxoside and [ 3 H]digitoxigenin monodigitoxoside has been investigated in vitro using rat liver microsomes. During a 40-min incubation period, the conjugation of digitoxigenin monodigitoxoside was five times greater than of digoxigenin monodigitoxoside at a substrate concentration of 5 μm and three times greater at a 20 μM substrate concentration. No difference in conjugation rates was observed between male and female rats, with either substrate. Pretreatment with spironolactone (100 mg/kg/day for 3 days) stimulated the conjugation of both substrates in females, but no significant changes were observed in males with either substrate. Pretreatment (75 mg/kg/day) with pregnenolone-16α-carbonitrile (PCN) caused enhanced glucuronidation of both substrates in both sexes. The conjugation rates in the PCN-pretreated rats were approximately twice those of the spironolactone-pretreated rats. The possible role of this increased conjugation in the protective effect of spironolactone and PCN against digitalis toxicity is discussed.