The metabolic disposition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the induced mouse.
The toxicokinetics of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a member of the aminoimidazoazaarene family of mutagens, was studied in C57BL/6 male mice after ip and gavage exposure to a single dose of 100 mg/kg body weight. Twenty-four hr after administration of the dose, 39% of the [14C]PhIP had been found in the urine of the animals exposed ip and 12% had been found in the faeces. By comparison, at 24 hr, gavage-exposed animals had excreted 31% of the administered radioactivity in the urine and 30% in the faeces. Significantly higher levels of labelled compounds could be detected in the blood of animals dosed ip than in that of those dosed by gavage at 6 and 12 hr after dosing. Tissue concentrations of labelled compound were highest in the liver and gastro-intestinal tract of the ip group and the large intestine of the gavage group. Considerable radioactivity was also detected in the contents of the large and small intestine of the ip group suggesting biliary excretion of PhIP. Peak tissue concentrations were found 6-12 hr after administration of the dose by both routes. High-performance liquid chromatography of urine demonstrated the presence of 11 metabolites while only two major metabolites were found in the faeces, one of which was not present in the urine. None of the metabolites appeared to be formed by simple N-acetylations or N-demethylations of PhIP. No differences were seen in the metabolite profiles between the ip and the gavage groups, but significant differences were seen in the kinetics of PhIP excretion between animals dosed by these two routes. These data indicate that the toxicokinetics of PhIP metabolism differ depending on the route of administration and should be considered when performing animal studies to assess the significance of human dietary PhIP consumption.
Turteltaub
K W
KW
Biomedical Sciences Division, Lawrence Livermore National Laboratory, Livermore, CA 94550.
Knize
M G
MG
Healy
S K
SK
Tucker
J D
JD
Felton
J S
JS
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000032:analysis; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution; D014556:Urine / Q000032:analysis
D001140:Aroclors; D002250:Carbon Radioisotopes; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine