title: Inhibition of antipyrine metabolite formation. Steady state studies with cimetidine and metyrapone in rats.
abstract: Antipyrine metabolite kinetics have been characterized in rats receiving an intravenous infusion of either saline, cimetidine, or metyrapone. 14CO2 exhalation rate-time profiles following [N-methyl-14C] antipyrine administration demonstrate that, when either cimetidine or metyrapone is maintained at a steady state plasma concentration, a constant degree of inhibition is evident. Under the conditions imposed in this in vivo study, the inhibitory potency of metyrapone is approximately 6 times that observed with cimetidine. Rate constants for the formation of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine have been calculated using breath and urinary metabolite data under the steady state inhibitory states. Metyrapone nonselectively inhibits the formation of all three oxidative metabolites by approximately one-third. Cimetidine inhibition is selective where rates of 3-methyl-hydroxylation and N-demethylation are reduced by 50% yet 4-hydroxylation is unaffected. The value of assessing inhibitory responses under steady state conditions is discussed and the nonlinear nature of the kinetics of inhibition, when a single bolus dose of inhibitor is used, is illustrated by means of computer simulation.
authors.forename: P N
authors.initials: PN
authors.lastname: Shaw
authors.forename: J
authors.initials: J
authors.lastname: Tseti
authors.forename: S
authors.initials: S
authors.lastname: Warburton
authors.forename: A
authors.initials: A
authors.lastname: Adedoyin
authors.forename: J B
authors.initials: JB
authors.lastname: Houston
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000652:urine; D002245:Carbon Dioxide / Q000096:biosynthesis; D002927:Cimetidine / Q000494:pharmacology*; D000077553:Edaravone; D007700:Kinetics; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002245:Carbon Dioxide; C007983:4-hydroxyantipyrine; C031820:3-hydroxymethylantipyrine; D002927:Cimetidine; D000077553:Edaravone; D000983:Antipyrine; D008797:Metyrapone