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 hexobarbital 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 (Clm AP), R-HB (Clm R-HB) and S-HB (Clm S-HB) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-->HMA), 4-hydroxyantipyrine (Cl-->OHA) and norantipyrine (Cl-->NORA). Aging appeared to have little influence on the pharmacokinetics of the model compounds. By contrast, the influence of PB pretreatment on Clm AP changed 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 clearances of formation of the three metabolites differentially. Clm S-HB was about six times higher than Clm R-HB without induction. After PB induction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly decreased Clm S-HB when compared with the uninduced state. The extent of induction of R-HB metabolism had decreased strongly at 24 and 30 months. The present results clearly indicate that in the aged rat, the P450 enzyme system is much less sensitive to PB induction.
Groen
K
K
TNO Institute of Ageing and Vascular Research, Leiden, The Netherlands.
Breimer
D D
DD
Jansen
E J
EJ
van Bezooijen
C F
CF
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004790:Enzyme Induction; D006591:Hexobarbital / Q000493:pharmacokinetics*; D008137:Longitudinal Studies; D008297:Male; D008657:Metabolic Clearance Rate; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D013237:Stereoisomerism
D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D000983:Antipyrine; D010634:Phenobarbital