Metabolism of simultaneously administered antipyrine and theophylline in male BN/BiRij rats before and after induction with 3-methylcholanthrene.
In order to study the metabolic activities of different P-450 enzymes in male Brown Norway rats, formation rates of antipyrine (AP) metabolites and theophylline (TH) metabolic clearance were determined. Brown Norway rats are often used in studies concerning the influence of age on liver function. Experiments were performed after simultaneous iv administration of the two compounds with and without 3-methylcholanthrene (3-MC) pretreatment. Pharmacokinetic data of both AP and TH were significantly influenced by 3-MC pretreatment. Metabolic clearance of AP increased from 6.8 +/- 1.0 (mean +/- SD, N = 23) to 18.4 +/- 7.9 (N = 10) ml.min-1.kg-1, whereas the metabolic clearance of TH increased from 1.9 +/- 0.6 to 20.0 +/- 5.1 ml.min-1.kg-1. Elimination half-life in plasma decreased from 77 +/- 10 to 33 +/- 9 min for AP and from 171 +/- 36 to 25 +/- 7 min for TH, respectively. Urinary recovery as the metabolites 3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine accounted for approximately 36% of the administered dose in the control situation, and for approximately 21% after 3-MC pretreatment. 3-MC pretreatment strongly reduced the formation of 3-hydroxymethylantipyrine, but increased the formation rate of 4-hydroxyantipyrine and norantipyrine. Weak correlations were found between the clearances of formation of the AP metabolites and the metabolic clearance (CLm) of TH in the control rats. This may be caused by a large contribution of constitutive P-450 enzymes in the formation of AP metabolites and/or the metabolic clearance of TH in Brown Norway rats.(ABSTRACT TRUNCATED AT 250 WORDS)
TNO Institute for Ageing and Vascular Research, Leiden, The Netherlands.
K
K
Groen
D D
DD
Breimer
C F
CF
van Bezooijen
D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008748:Methylcholanthrene / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism*
D008748:Methylcholanthrene; D013806:Theophylline; D000983:Antipyrine