THE INFLUENCE OF AGING ON THE METABOLISM OF SIMULTANEOUSLY ADMINISTERED HEXOBARBITAL ENANTIOMERS AND ANTIPYRINE BEFORE AND AFTER PHENOBARBITAL INDUCTION IN MALE-RATS - A LONGITUDINAL-STUDY

The influence of aging on the metabolism of antipyrine (AP) and hexoba rbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12 , 24 and 30 months. The metabolic clearances of AP (Cl-mAP), R-HB (Cl- mR-HB) and S-HB (Cl-mS-HB) were used as indicators for P450 enzyme act ivities in vivo. This also included the assessment of the clearances o f formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-HMA ), 4-hydroxyantipyrine (CL(oHA)) and norantipyrine (CL(NORA)) Aging ap peared to have little influence on the pharmacokinetics of the model c ompounds. By contrast, the influence of PB pretreatment on CI, AP chan ged dramatically with aging. The extent of induction decreased from 4. 5-fold at 6 months to 1.7-fold at 30 months. Aging influenced the clea rances of formation of the three metabolites differentially. CI, S-HB was about six times higher than CI, R-HB without induction. After PB i nduction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly d ecreased CI, S-HB when compared with the uninduced state. The extent o f. induction of R-HB metabolism had decreased strongly at 24 and 30 mo nths. The present results clearly indicate that in the aged rat, the P 450 enzyme system is much less sensitive to PB induction.