Pharmacokinetics of diphenhydramine after dose ranging in nonpregnant ewes.
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.
Yoo
S D
SD
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Axelson
J E
JE
Kwan
E
E
Rurak
D W
DW
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002245:Carbon Dioxide / Q000097:blood; D004155:Diphenhydramine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D010100:Oxygen / Q000097:blood; D011485:Protein Binding; D012756:Sheep
D001798:Blood Proteins; D002245:Carbon Dioxide; D004155:Diphenhydramine; D010100:Oxygen