Pharmacokinetics of beta-methyldigoxin in healthy humans I: intravenous studies

The pharmacokinetics of intravenously administered solutions of 0.30-and 0.60-mg bolus doses of 3H-beta-methyldigoxin, labeled in the 12alpha-position, were dose independent. Individual radioactivities assignable to the parent drug and specifically identified metabolites after TLC separation were followed in the plasma, urine, and feces. A sum of four exponentials described the plasma beta-methyldigoxin data with apparent half-lives of 0.04, 0.33, 3.5, and 41 hr. beta-Methyldigoxin was 10% plasma protein bound and had a red blood cell-plasma water partition coefficient of 0.9. The only significant metabolite observed in plasma was digoxin, although glucuronides and sulfates of beta-methyldigoxin, digoxin and digoxigenin also were observed in urine. As much as 92 +/- 3% of the dose was excreted by all processes by 144 hr. Of this amount, renal excretion accounted for fractions that were 0.47 unchanged, 0.35 digoxin, and 0.058 water-soluble metabolites. The fraction in the feces was 0.13. The urine flow independent renal clearances of beta-methyldigoxin and derived digoxin were 59 and 206 ml/min, respectively. The metabolism was a relatively fast process. The terminal pseudo-steady-state elimination of beta-methyldigoxin with a half-life of 41 hr was reached 27 hr after drug administration and was primarily dependent on the slow release of sequestered or distributed drug drom the tissues into the central compartment. The drug and metabolite levels in plasma and urine were consistent with analog computer fitting to the proposed pharmacokinetic multicompartmental model.