Differential effects of enzyme induction on antipyrine metabolite formation.

Abstract

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine.

“…N-demethylation, however, appeared unaffected by the pretreatment with phenytoin and carbamazepine. These data are in contrast to previous studies which have reported enhanced demethylation as the major contributing factor in the raised antipyrine total clearance (Danhof et al, 1982b;D0ssing et al, 1983;Staiger et al, 1983;Toverud et al, 1981). An earlier study in man had also indicated an enhancement of 4-hydroxylation of antipyrine (Petruch et al, 1974).…”

“…The control urinary 4H recoveries reported in this study (36.1 ± 4.7 and 31.5 ± 8.5% of dose for the phenytoin and carbamazepine studies, respectively, before treatment) are slightly higher than those reported by some workers (Danhof et al, 1982b;Toverud et al, 1981) but are of the same order (38.3 ± 2.0%) as reported by Bottcher et al (1982). Both 3HM (12.5 + 2.0% and 12.1 + 2.0%) and Nor (15.5 ± 3.3% and 13.6 + 4.6%) control recoveries are of similar magnitudes to those previously reported.…”

“…It was therefore to be expected that the antipyrine formation clearances during the pre-dosing study would correspond to those in previous studies (Danhof et al, 1982b;Toverud et al, 1981;Staiger et al, 1983;D0ssing et al, 1983) for normal human volunteers. Following dosing with phenytoin and carbamazepine a differential effect on antipyrine metabolism can be observed.…”

“…Five situations of induction have been studied in man with regard to their effects on antipyrine metabolite kinetics; pretreatment with pentobarbitone (Danhof et (Toverud et al, 1981), sulphinpyrazone (Staiger et al, 1983) and phenobarbitone (D0ssing et al, 1983) and autoinduction (Danhof et al, 1982b).…”

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

“…Another major improvement in the value of antipyrine as a model substrate for assessing hepatic drug-metabolizing enzyme activity was made by the estimation of the rates of formation of antipyrine metabolites (Danhof et al, 1979b), because it is likely that different isoenzymes of the mixed-function oxygenase (MFO) system are involved in the formation of the different metabolites of antipyrine in man and rat (Danhof et al, 1979a(Danhof et al, , 1982aToverud et al, 1981;Teunissen et al, 1983a). Hence the activity of various isoenzymes of cytochrome P-450 may be measured with the aid of one compound (Breimer, 1983).…”