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Pharmacokinetics of Diphenhydramine after Dose Ranging in Nonpregnant Ewes

Authors :
Dan W. Rurak
Eddie Kwan
James E. Axelson
S.D. Yoo
Source :
Journal of Pharmaceutical Sciences. 79:106-110
Publication Year :
1990
Publisher :
Elsevier BV, 1990.

Abstract

Studies were conducted to characterize the pharmacokinetics of diphenhydramine in nonpregnant ewes after iv administration of 25-, 50-, 100-, and 200-mg doses of diphenhydramine hydrochloride on a crossover basis. Plasma drug concentration versus time data exhibited multiexponential characteristics. The initial distribution half-life increased from 5 to 9 min and the elimination half-life from 34 to 68 min as the dose was increased. There was also an increase in the volume of distribution (from 3 to 6 L/kg) with increasing dose. The elimination half-life and the volume of distribution after a 200-mg dose were significantly greater than after a 25-mg dose. There was, however, a linear increase in AUC0 infinity as dose was increased. The average total body clearance (approximately 5 L/h/kg) remained unchanged regardless of dose. The free fraction of diphenhydramine determined by equilibrium dialysis averaged 0.229 +/- 0.080, and the extent of drug binding to plasma protein was independent of the drug concentrations encountered (30-780 ng/mL) in the nonpregnant sheep in vivo. Concentration-independent binding of the drug was also confirmed by in vitro binding studies over the drug concentration range 10-2000 ng/mL. Therefore, it appears that changes in the volume of distribution are likely to be a result of changes in tissue uptake or binding of the drug as a function of dose.

Details

ISSN :
00223549
Volume :
79
Database :
OpenAIRE
Journal :
Journal of Pharmaceutical Sciences
Accession number :
edsair.doi.dedup.....c79fa21fef4ea6ff14d6057cd360a829
Full Text :
https://doi.org/10.1002/jps.2600790206