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Effect of cytochrome P-450 and flavin-containing monooxygenase modifying factors on the in vitro metabolism of amiodarone by rat and rabbit.
Drug Metab Dispos. 1987 Jul-Aug; 15(4):511-7.DM

Abstract

Experiments were conducted to affirm hepatic cytochrome P-450 involvement in the biotransformation of the class III antiarrhythmic agent, amiodarone (Am; Cordarone X) to its major metabolite, desethylamiodarone (DEA). Male Sprague-Dawley rats and male New Zealand white rabbits were treated with phenobarbital (PB) or 3-methylcholanthrene (3-MC) (to induce cytochrome P-450 (PB-inducible cytochrome(s) P-450) or P-448 (MC-inducible cytochrome P-450). In vivo decreases in rat hepatic microsomal cytochrome P-450 were achieved either by a single ip dose of CCl4 or by a 2-day treatment with CoCl2. In vitro biotransformation of Am by hepatic microsomes from PB-induced and 3-MC-induced rats and PB-induced rabbits was significantly greater than that from noninduced animals. Conversely, in vitro DEA production was significantly decreased with hepatic microsomes from CCl4- and CoCl2-pretreated rats. The classic P-450 inhibitors, piperonyl butoxide, SKF 525A, n-octylamine, and CO provided a significant reduction in the in vitro formation of DEA by microsomes from induced animals. In vitro DEA formation by hepatic microsomes from PB- and 3-MC-induced rats was significantly decreased by 0.5 mM chloroquine (specific inhibitors of PB-inducible cytochrome(s) P-450) and 0.3 mM quinacrine (specific inhibitor of MC-inducible cytochrome(s) P-450), respectively. Further evidence for involvement of gut microsomal flavin-containing monooxygenase was provided by the inhibition of gut microsomal-mediated in vitro DEA formation in the presence of methimazole. Methimazole had no effect on hepatic microsomal DEA production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Department of Pharmacology and Toxicology, University of Mississippi Medical Center.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2888625

Citation

Young, R A., and H M. Mehendale. "Effect of Cytochrome P-450 and Flavin-containing Monooxygenase Modifying Factors On the in Vitro Metabolism of Amiodarone By Rat and Rabbit." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 15, no. 4, 1987, pp. 511-7.
Young RA, Mehendale HM. Effect of cytochrome P-450 and flavin-containing monooxygenase modifying factors on the in vitro metabolism of amiodarone by rat and rabbit. Drug Metab Dispos. 1987;15(4):511-7.
Young, R. A., & Mehendale, H. M. (1987). Effect of cytochrome P-450 and flavin-containing monooxygenase modifying factors on the in vitro metabolism of amiodarone by rat and rabbit. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 15(4), 511-7.
Young RA, Mehendale HM. Effect of Cytochrome P-450 and Flavin-containing Monooxygenase Modifying Factors On the in Vitro Metabolism of Amiodarone By Rat and Rabbit. Drug Metab Dispos. 1987 Jul-Aug;15(4):511-7. PubMed PMID: 2888625.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of cytochrome P-450 and flavin-containing monooxygenase modifying factors on the in vitro metabolism of amiodarone by rat and rabbit. AU - Young,R A, AU - Mehendale,H M, PY - 1987/7/1/pubmed PY - 1987/7/1/medline PY - 1987/7/1/entrez SP - 511 EP - 7 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 15 IS - 4 N2 - Experiments were conducted to affirm hepatic cytochrome P-450 involvement in the biotransformation of the class III antiarrhythmic agent, amiodarone (Am; Cordarone X) to its major metabolite, desethylamiodarone (DEA). Male Sprague-Dawley rats and male New Zealand white rabbits were treated with phenobarbital (PB) or 3-methylcholanthrene (3-MC) (to induce cytochrome P-450 (PB-inducible cytochrome(s) P-450) or P-448 (MC-inducible cytochrome P-450). In vivo decreases in rat hepatic microsomal cytochrome P-450 were achieved either by a single ip dose of CCl4 or by a 2-day treatment with CoCl2. In vitro biotransformation of Am by hepatic microsomes from PB-induced and 3-MC-induced rats and PB-induced rabbits was significantly greater than that from noninduced animals. Conversely, in vitro DEA production was significantly decreased with hepatic microsomes from CCl4- and CoCl2-pretreated rats. The classic P-450 inhibitors, piperonyl butoxide, SKF 525A, n-octylamine, and CO provided a significant reduction in the in vitro formation of DEA by microsomes from induced animals. In vitro DEA formation by hepatic microsomes from PB- and 3-MC-induced rats was significantly decreased by 0.5 mM chloroquine (specific inhibitors of PB-inducible cytochrome(s) P-450) and 0.3 mM quinacrine (specific inhibitor of MC-inducible cytochrome(s) P-450), respectively. Further evidence for involvement of gut microsomal flavin-containing monooxygenase was provided by the inhibition of gut microsomal-mediated in vitro DEA formation in the presence of methimazole. Methimazole had no effect on hepatic microsomal DEA production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/2888625/Effect_of_cytochrome_P_450_and_flavin_containing_monooxygenase_modifying_factors_on_the_in_vitro_metabolism_of_amiodarone_by_rat_and_rabbit_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2888625 DB - PRIME DP - Unbound Medicine ER -