Identification of cytochrome P450 3A1/2 as the major P450 isoform responsible for the metabolism of fentanyl by rat liver microsomes

Anesth Analg. 1996 May;82(5):936-41. doi: 10.1097/00000539-199605000-00008.

Abstract

The metabolism of fentanyl was investigated using rat liver microsomes to determine whether fentanyl is metabolized by rat liver microsomal cytochrome P450 and, if so, which isoform is responsible for the metabolism. Microsomes isolated from rats pretreated with phenobarbital were more active in metabolizing fentanyl than were microsomes from saline controls. The major metabolic pathway of fentanyl was an oxidative N-dealkylation to norfentanyl, which was detected by a gas chromatograph-mass selective detector (GC-MSD) method. The apparent Vm values for microsomes isolated from saline- and phenobarbital-treated rats were 2 and 9 nmol norfentanyl.min-1.mg-1 microsomal protein, and the apparent Km values were 32 and 47 microM, respectively. Fentanyl metabolism was inhibited by antibodies specific for CYP3A1/2, as well as by chemical inhibitors specific for CYP3A. These results indicate that CYP3A1/2 plays a major role in the oxidation of fentanyl to norfentanyl by rat liver microsomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Intravenous / metabolism*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antifungal Agents / pharmacology
  • Aryl Hydrocarbon Hydroxylases*
  • Benzoflavones / pharmacology
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / isolation & purification
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dealkylation
  • Enzyme Inhibitors / pharmacology
  • Erythromycin / pharmacology
  • Fentanyl / analogs & derivatives
  • Fentanyl / metabolism*
  • GABA Modulators / pharmacology
  • Gas Chromatography-Mass Spectrometry
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / isolation & purification
  • Isoenzymes / metabolism*
  • Ketoconazole / pharmacology
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / isolation & purification
  • Mixed Function Oxygenases / metabolism*
  • Oxidation-Reduction
  • Phenobarbital / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Chloride

Substances

  • Anesthetics, Intravenous
  • Anti-Bacterial Agents
  • Antifungal Agents
  • Benzoflavones
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • GABA Modulators
  • Isoenzymes
  • norfentanyl
  • Sodium Chloride
  • Erythromycin
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A
  • Ketoconazole
  • Fentanyl
  • Phenobarbital