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Abstract
1. The effects of treating rats with the inducers phenobarbitone (4 × 80 mg/kg per day) and 3-methylcholanthrene (80 mg/kg) on the kinetics of the formation of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated.
2. Phenobarbitone treatment significantly increased the Vmax of 4-hydroxyantipyrine formation (by 2.3-fold) and of norphenazone formation (by 2.3-fold). 3-Methylcholanthrene treatment caused a slight, but significant (P <0.05), reduction in Vmax for 3-hydroxy-methylantipyrine formation.
3. Phenobarbitone markedly reduced the Km for 3-hydroxymethylantipyrine formation (from 2.2 ± 0.5 mM to 0.65 ± 0.09 mM), whereas 3-methylcholanthrene treatment resulted in an increase (P<0.05) in the Km (to 4.9 ± 1.1 mM). The only other significant change in Km was a slight decrease in that of 4-hydroxyantipyrine formation following phenobarbitone treatment (from 4.6 ± 1.1 mM to 2.2±0.3 mM, P<0.05).
4. Calculation of the ratio Vmax/Km permitted an estimate of the clearance in vivo to the metabolites. There was good agreement between predicted values and those for total body clearance of antipyrine, and for changes in clearance to individual metabolites in vivo following treatment with enzyme inducers.
5. Kinetic analysis of formation of antipyrine metabolites in vitro has enabled the enzymic basis for changes observed in their excretion to be established. Further evidence was also obtained for the involvement of multiple forms of cytochrome P-450 in antipyine oxidation.