Glucuronidation in the chimpanzee (Pan troglodytes): studies with acetaminophen, oestradiol and morphine.
The chimpanzee has recently been characterized as a surrogate for oxidative drug metabolism in humans and as a pharmacokinetic model for the selection of drug candidates. In the current study, the glucuronidation of acetaminophen, morphine and oestradiol was evaluated in the chimpanzee to extend the characterization of this important animal model. Following oral administration of acetaminophen (600 mg) to chimpanzees (n=2), pharmacokinetics were comparable with previously reported human values, namely mean oral clearance 0.91 vs. 0.62+/-0.05 l h-1 kg-1, apparent volume of distribution 2.29 vs. 1.65+/-0.25 l kg-1, and half-life 1.86 vs. 1.89+/-7h, for chimpanzee vs. human, respectively. Urinary excretions (percentage of dose) of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were also similar between chimpanzees and humans, namely 2.3 vs. 5.0, 63.1 vs. 54.7, and 25.0 vs. 32.3%, respectively. Acetaminophen, oestradiol and morphine glucuronide formation kinetics were investigated using chimpanzee (n=2) and pooled human liver microsomes (n=10). V(max) (app) and K(m)(app) (or S(50)(app)) for acetaminophen glucuronide, morphine 3- and 6-glucuronide, and oestradiol 3- and 17-glucuronide formation were comparable in both species. Eadie-Hofstee plots of oestradiol 3-glucuronide formation in chimpanzee microsomes were characteristic of autoactivation kinetics. Western immunoblot analysis of chimpanzee liver microsomes revealed a single immunoreactive band when probed with anti-human UGT1A1, anti-human UGT1A6, and anti-human UGT2B7. Taken collectively, these data demonstrate similar glucuronidation characteristics in chimpanzees and humans.
Wong
H
H
Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS 86, South San Francisco, CA 94080, USA. wong.harvey@gene.com
Grace
J E
JE
Wright
M R
MR
Browning
M R
MR
Grossman
S J
SJ
Bai
S A
SA
Christ
D D
DD
D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002679:Pan troglodytes / Q000378:metabolism*; D013045:Species Specificity
D020719:Glucuronides; D000082:Acetaminophen; D004958:Estradiol; D009020:Morphine