Effect of dose volume on the toxicokinetics of acrylamide and its metabolites and 2-deoxy-D-glucose.
Acrylamide (AA) is a known mutagen and animal carcinogen. Comparison of recent studies revealed significant quantitative differences in AA-induced germ cell mutagenicity. It was hypothesized that despite the administration of AA at similar doses, the discrepancy in the observed effects was most likely due to varying AA concentrations in the administered dosing solution. To test this hypothesis, AA was administered i.p. to mice at 50 mg/kg in a dose volume of 5 or 50 ml/kg, blood was collected at various time points, and AA and its metabolites were quantitated. Changes in dose volume resulted in significant differences in the toxicokinetics of AA and its metabolites and suggested that increased C(max) of AA led to increased metabolism. This theory, in conjunction with the fact that higher levels of AA-derived radioactivity were detected in the testes, may explain the greater toxicity of a 50 mg/kg dose when administered in 5 versus 50 ml/kg. The impact of dose volume on the toxicokinetics of 2-deoxy-d-glucose (DG), a nonreactive, nonmetabolizable substance, was also investigated. The areas under the curve for DG were not different for the two dose volumes; however, C(max) for the more concentrated dose was significantly higher. In conclusion, current studies show that the toxicokinetics of an administered xenobiotic and its metabolites is influenced by the concentration of the parent chemical in the dosing solution. Therefore, it is important to consider the concentration of an administered xenobiotic in the dosing solution because it may affect its toxicokinetics and metabolism and subsequently affect the biological effects of the administered chemical.
Ghanayem
Burhan I
BI
Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Ghanayem@niehs.nih.gov
Bai
Re
R
Burka
Leo T
LT
D020106:Acrylamide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D003847:Deoxyglucose / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds; D005947:Glucose / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization
D002273:Carcinogens; D004852:Epoxy Compounds; D009153:Mutagens; D020106:Acrylamide; D003847:Deoxyglucose; D005947:Glucose