Inhibition of antipyrine metabolite formation. Steady state studies with cimetidine and metyrapone in rats

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.