The pharmacokinetics of digoxin in newborn and adult sheep

Abstract

The pharmacokinetics of digoxin were determined in 12 ewes and 13 newborn sheep after bolus drug administration and under steady state drug conditions. After death, tissue distribution of digoxin was determined and normalized to plasma drug concentrations at steady state. Volume of distribution and total drug clearance were lower at steady state than the comparable variables calculated from bolus drug administration. No significant difference between ewes and newborns was shown for drug distribution half-life (0.72 vs. 0.76 hr), drug elimination half-life (15.2 vs. 13.7), or renal drug clearance (0.86 vs. 0.89 liters/kg/hr). Total drug clearance as well as the area derived and steady state volumes of distribution were higher in newborns than in ewes. Digoxin secretion into the urine was limited in newborns, as evidenced by a lower renal digoxin clearance to creatinine clearance ratio in newborns than in ewes (371 vs. 600%). The plasma concentration of digoxin at steady state correlated well with myocardial drug concentrations. Drug distribution was similar in both age groups; however, the tissue to plasma digoxin ratio in kidney was higher in newborns than in ewes (mean 469 vs. 263, respectively). Although age-related differences in drug clearance and distribution volume existed, intersubject variation was substantial, and the demonstrated variations were not large enough to account for the high doses of digoxin used to treat congestive heart failure in immature subjects.

Toxicokinetics of cotyledoside following intravenous administration to sheep

“…Cotyledoside is so toxic at minute concentrations that detection of plasma concentrations becomes problematic. In 2 studies designed to determine digoxin pharmacokinetics in adult sheep the therapeutic dose administered intravenously varied from 50-75 µg/kg 1,4 . In the current study signs of toxicity were induced after a single intravenous injection of 27 µg cotyledoside/ kg.…”

“…Pharmacokinetic variables have been determined for digoxin, a cardenolide cardiac glycoside. A distribution half-life (t½") of 0.72 h and an elimination half-life (t½$) of 15.2 h have been determined in ewes 1 . In another study a t½ $ of 7.15 h was calculated for sheep 4 .…”

Effects of Ouabain on Monovalent Cation Transport in Mammalian Tissue

“…Newborn (NB) and adult (Ad) sheep myo specimens were used so that data could be compared with pharmacokinetic and physiologic studies performed previously [1,14].…”

“…The weight-related doses of cardiac glycosides used to treat congestive heart failure vary substantially with age [1][2][3][4][5]. Although drug tolerance is higher in immature subjects than in nature ones [1,6,7], no consistent age-related differences in drug binding, drug metabolism or drug distribu tion within the body have been found [1,[8][9][10][11], The small pharmacokinetic differences in digoxin handling by newborn and adult sheep do not explain Supported in part by NIH grant No.…”

“…HL23980. the large differences in therapeutic regimes used in newborn and adult humans [1,6,12,13]. A series of studies suggest the physiologic effects of cardiac glycosides vary with age [6,14,15], but the reasons for this varia tion remain unsettled [9,[16][17][18].…”