Drug disposition and biotransformation in the developing beagle dog.
The ability of developing male and female beagle pups to biotransform and eliminate drugs was studied by administering single intravenous doses of acetaminophen (50 mg/kg body wt), phenobarbital (15 mg/kg body wt), or phenytoin (15 mg/kg body wt) to the same groups of dogs (n = 6-8/drug) at 4, 10, 20, 40, and 60 days of age. At suitable intervals after treatment, small (1.0 ml) blood samples were obtained via the jugular vein and centrifuged and the plasma was recovered and stored at -20 degrees C to await analysis. Acetaminophen proved to be the most interesting "probe" of function with the plasma elimination half-life (beta t/2) in 40- to 60-day-old pups being 4.5-fold shorter than at 4 days of age. The synthesis of sulfate-conjugated drug decreased with age. In older pups, the synthesis of the glucuronide-conjugated drug was predominant. The elimination of sulfated acetaminophen from plasma was slow at all ages whereas the rate of glucuronide disappearance increased with age. Phenobarbital was slowly eliminated from the plasma at all ages and there was no indication of p-hydroxylated metabolite formation. The plasma beta t/2 of phenytoin decreased dramatically with age, a 10-fold difference occurring between 4- and 60-day-old pups. para-Hydroxylated phenytoin (pHPPH) was detected only in the plasma of 4- and 10-day-old pups, the plasma beta t/2 decreasing with age. With the appropriate chemical and using the technique of collecting small, serial blood samples, this animal model can be potentially useful in perinatal toxicity studies.
Ecobichon
D J
DJ
Department of Pharmacology and Therapeutics, McGill University Montréal, Quebec, Canada.
D'Ver
A S
AS
Ehrhart
W
W
D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics; D000375:Aging / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005260:Female; D006207:Half-Life; D008297:Male; D010599:Pharmacokinetics; D010634:Phenobarbital / Q000378:metabolism / Q000493:pharmacokinetics; D010672:Phenytoin / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D014462:Ultrafiltration
D001798:Blood Proteins; D000082:Acetaminophen; D010672:Phenytoin; D010634:Phenobarbital