RT Journal Article
SR Electronic
T1 INCREASED CLEARANCE OF DIGOXIN IN RABBITS DURING REPEATED ADMINISTRATION
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 516
OP 524
VO 205
IS 2
A1 HERMANN R. OCHS
A1 GUNTHER BODEM
A1 GERD BALES
A1 DAVID J. GREENBLATT
A1 THOMAS W. SMITH
YR 1978
UL http://jpet.aspetjournals.org/content/205/2/516.abstract
AB The pharmacokinetics of digoxin were studied in three groups of rabbits. In the first two groups, radioimmunoassay was used as the analytic technique. After single i.v. doses of 0.8 mg (0.239 mg/kg) of digoxin, disappearance of digoxin from serum had three exponential phases. The mean (±S.E.) apparent elimination half-life for radioimmunoassayable digoxin was 14.8 ± 3.2 hours. With daily 0.8-mg injections of digoxin to eight female rabbits, mean (±S.E.) serum concentrations at 12 and 24 hours after the first dose were 0.62 ± 0.06 and 0.21 ± 0.03 ng/ml, respectively. After the seventh dose, these values fell to 0.23 ± 0.09 and 0.09 ± 0.04 ng/ml, respectively, significantly lower than the predicted concentrations (P< .01). The third group of animals received 0.2 mg/kg of digoxin daily for 13 days. The first and 13th doses included 216 µCi of [3H]digoxin, labeled in the C12 position. Disappearance of total serum radioactivity had three exponential phases after both doses, and kinetic parameters as determined from 3H-counts were not significantly different. The apparent elimination half-life of serum radioactivity was 33.9 ± 1.8 hours. Recovery of radioactivity was 15% in urine and 75% in the feces over 96 hours after both doses. The amount of chloroform-extractable radioactivity in serum and urine tended to be higher after the first dose, but the differences generally did not reach significance. After incubation of urine with hydrochloric acid and with glucuronidase-sulfatase, chloroform-extractable radioactivity more than doubled after both doses. Thus, digoxin is extensively metabolized by the rabbit. Digoxin clearance measured by the more specific radioimmunoassay is greater than that determined from total serum radioactivity. During repeated administration, plateau levels of immunoassayable digoxin progressively fall, suggesting that digoxin stimulates its own clearance. This change in clearance is not reflected by the pharmacokinetics of total radioactivity. 1978 By The Williams & Wilkins Company