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 (CL(m)) 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. However, in the 3-MC pretreated rats, a strong correlation was found between the formation clearance of 4-hydroxyantipyrine and CL(m) of TH, indicating that the same or closely related P-450 enzymes (probably the 3-MC-inducible enzymes IA1 and IA2) are involved in both pathways. Furthermore, it seems that in Brown Norway rats, alternative pathways are available for the metabolism of AP. This type of basic information is important in order to determine subsequently the influence of aging on the correlation between the clearance of formation of 4-hydroxyantipyrine and the metabolic clearance of TH.