On the antipyrine test in laboratory animals. Studies in the dog and monkey.
The antipyrine (AP) test has been challenged in species other than humans on the grounds that, in some nonhuman species, particularly on induction, hepatic blood flow may become as prominent a factor in AP clearance as hepatic metabolism. Therefore, we investigated in dogs and monkeys the disposition of AP to determine how well AP serves as a model drug to indicate changes in rates of hepatic clearance. After administration of an oral solution of AP (5 mg/kg) to control dogs, the percentage of the dose absorbed was 98%, based on urinary and fecal excretion of AP and its metabolites. Despite complete AP absorption, absolute bioavailability of AP was 78 +/- 12% under basal conditions, suggesting that AP does undergo some degree of presystemic elimination, approximately 22%. After PB administration of 20 mg/kg/day for 9 days, po, AP bioavailability decreased to 60 +/- 14%. The systemic clearance of AP increased from 9.4 +/- 2.3 ml/min/kg under basal conditions to 27.5 +/- 4.6 ml/min/kg following PB. PB decreased mean plasma AP half-life from 71.5 min under basal conditions to 27.7 min, and mean hepatic blood flow increased from 0.49 liters/min to 0.63 liters/min. Induction doubled the hepatic extraction ratio for AP to 0.4 from 0.2 under basal conditions. In beagle dogs after PB pretreatment, 97% of the total systemic clearance of AP was estimated to be due to enhanced hepatic AP metabolism, only 3% to increased hepatic blood flow. Therefore, for dogs under both basal and induced conditions it is concluded that AP clearance reflects predominantly hepatic AP metabolism, being negligibly influenced by hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Vickers
F F
FF
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033.
Bowman
T A
TA
Dvorchik
B H
BH
Passananti
G T
GT
Hughes
D M
DM
Vesell
E S
ES
D000284:Administration, Oral; D000818:Animals; D000983:Antipyrine / Q000494:pharmacology; D001682:Biological Availability; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004285:Dogs / Q000502:physiology*; D005243:Feces / Q000032:analysis; D005260:Female; D007262:Infusions, Intravenous; D008111:Liver Function Tests; D008251:Macaca / Q000502:physiology*; D013997:Time Factors
D000983:Antipyrine