Antipyrine metabolite kinetics in rats: studies on dose and time dependence.
Antipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4-hydroxylation, benzylic oxidation, and N-demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25-500 mg kg-1. By using [N-methyl-14C]-antipyrine, the single carbon fragment lost by N-demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half-life estimate which, according to theoretical principles, reflects the antipyrine plasma half-life. When both half-lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg-1 and 500 mg kg-1 there is an increase in CER half-life (218 and 303 min respectively) when compared to a dose below 100 mg kg-1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25-100 mg kg-1. Although inter-rat variation in antipyrine metabolite kinetics was substantial, intra-rat variability was small. The noninvasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.
D000818:Animals; D000983:Antipyrine / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002245:Carbon Dioxide; D000983:Antipyrine