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Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes.
Pol J Pharmacol. 2001 Jan-Feb; 53(1):11-9.PJ

Abstract

The effects of pretreating rats with the inducers, phenobarbital or spironolactone, on the formation rate of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated. Both inducers reduced the rate of 3-methylhydroxylation of antipyrine by approximately 50%. In contrast, N-demethylation and 4-hydroxylation were enhanced 1.7-fold and 3.4-fold, respectively, in case of phenobarbital induction and 1.4-fold and 2.6-fold, respectively, following spironolactone treatment. To elucidate the role of some cytochrome P450 isoenzymes in the production of the three major metabolites of antipyrine, the effects of form selective enzyme inhibitors on antipyrine oxidation were also studied. Troleandomycin did not alter 3-methylhydroxylation but reduced both N-demethylation and 4-hydroxylation of antipyrine in microsomes from induced rat liver. Cimetidine and chloramphenicol decreased the rate of formation of all three metabolites in microsomes from induced and uninduced animal livers as well. Chloramphenicol seemed to be the most potent inhibitor of in vitro antipyrine oxidation. Alpha-methyldopa significantly enhanced the rate of formation of 4-hydroxyantipyrine and slightly reduced the rate of N-demethylation and 3-methylhydroxylation. According to the data obtained with microsomes from uninduced rat livers, the formation of the three major metabolites of antipyrine is extensively mediated by CYP2C11/C6. In microsomes from induced animal liver, CYP2B and CYP3A may contribute to both N-demethylation and 4-hydroxylation of antipyrine.

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Authors+Show Affiliations

Szakács T
Department of Biochemical Pharmacology, Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest. veres@chemres.hu
Veres Z
No affiliation info available
Vereczkey L
No affiliation info available

MeSH

AnimalsAnti-Bacterial AgentsAnti-Inflammatory Agents, Non-SteroidalAnticonvulsantsAntipyrineChloramphenicolCimetidineCytochrome P-450 Enzyme SystemDrug InteractionsEnzyme InductionEnzyme InhibitorsIn Vitro TechniquesMaleMethyldopaMicrosomes, LiverNADPOxidation-ReductionPhenobarbitalRatsRats, WistarSpironolactoneSympatholytics

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11785906

Citation

Szakács, T, et al. "Effect of Phenobarbital and Spironolactone Treatment On the Oxidative Metabolism of Antipyrine By Rat Liver Microsomes." Polish Journal of Pharmacology, vol. 53, no. 1, 2001, pp. 11-9.
Szakács T, Veres Z, Vereczkey L. Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes. Pol J Pharmacol. 2001;53(1):11-9.
Szakács, T., Veres, Z., & Vereczkey, L. (2001). Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes. Polish Journal of Pharmacology, 53(1), 11-9.
Szakács T, Veres Z, Vereczkey L. Effect of Phenobarbital and Spironolactone Treatment On the Oxidative Metabolism of Antipyrine By Rat Liver Microsomes. Pol J Pharmacol. 2001 Jan-Feb;53(1):11-9. PubMed PMID: 11785906.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes. AU - Szakács,T, AU - Veres,Z, AU - Vereczkey,L, PY - 2002/1/12/pubmed PY - 2002/6/14/medline PY - 2002/1/12/entrez SP - 11 EP - 9 JF - Polish journal of pharmacology JO - Pol J Pharmacol VL - 53 IS - 1 N2 - The effects of pretreating rats with the inducers, phenobarbital or spironolactone, on the formation rate of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated. Both inducers reduced the rate of 3-methylhydroxylation of antipyrine by approximately 50%. In contrast, N-demethylation and 4-hydroxylation were enhanced 1.7-fold and 3.4-fold, respectively, in case of phenobarbital induction and 1.4-fold and 2.6-fold, respectively, following spironolactone treatment. To elucidate the role of some cytochrome P450 isoenzymes in the production of the three major metabolites of antipyrine, the effects of form selective enzyme inhibitors on antipyrine oxidation were also studied. Troleandomycin did not alter 3-methylhydroxylation but reduced both N-demethylation and 4-hydroxylation of antipyrine in microsomes from induced rat liver. Cimetidine and chloramphenicol decreased the rate of formation of all three metabolites in microsomes from induced and uninduced animal livers as well. Chloramphenicol seemed to be the most potent inhibitor of in vitro antipyrine oxidation. Alpha-methyldopa significantly enhanced the rate of formation of 4-hydroxyantipyrine and slightly reduced the rate of N-demethylation and 3-methylhydroxylation. According to the data obtained with microsomes from uninduced rat livers, the formation of the three major metabolites of antipyrine is extensively mediated by CYP2C11/C6. In microsomes from induced animal liver, CYP2B and CYP3A may contribute to both N-demethylation and 4-hydroxylation of antipyrine. SN - 1230-6002 UR - https://www.unboundmedicine.com/medline/citation/11785906/Effect_of_phenobarbital_and_spironolactone_treatment_on_the_oxidative_metabolism_of_antipyrine_by_rat_liver_microsomes_ L2 - http://www.if-pan.krakow.pl/pjp/pdf/2001/1_11.pdf DB - PRIME DP - Unbound Medicine ER -

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