In vitro metabolic characterization, phenotyping, and kinetic studies of 9cUAB30, a retinoid X receptor-specific retinoid.

Academic Article

Abstract

  • The present study was conducted to compare the in vitro phase I and phase II metabolic profiles of (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30) in human, rat, and dog microsomes and to characterize and identify the associated metabolic kinetics and specific isozymes from human liver microsomes (HLM) responsible for metabolism, respectively. Data from these experiments revealed that nine (M1-M9) phase I metabolites along with a single glucuronide conjugate were observed across the species investigated. With the exception of glucuronidation, no evidence of metabolism was detected for phase II enzymes (data not shown). Significant differences between species with regard to metabolic profile, stability, and gender were noted. For the eight phase I metabolites detected in HLM, the specific isozymes responsible for the biotransformations were CYP2C8, CYP2C9, and CYP2C19, with minor contributions from CYP1A2 and CYP2B6. For the glucuronide conjugate, UGT1A9 was the major catalyzing enzyme, with a minor contribution from UGT1A3. Kinetic analysis of eight of the detected metabolites indicated that four seemed to follow classical hyperbolic kinetics, whereas the remaining four showed evidence of either autoactivation or substrate inhibition.
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    Keywords

  • Animals, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP2B6, Cytochrome P-450 Enzyme System, Dogs, Drug Stability, Fatty Acids, Unsaturated, Female, Glucuronides, Glucuronosyltransferase, Humans, In Vitro Techniques, Kinetics, Male, Metabolic Detoxication, Phase I, Metabolic Detoxication, Phase II, Microsomes, Liver, Models, Biological, Molecular Structure, Naphthalenes, Oxidation-Reduction, Oxidoreductases, N-Demethylating, Rats, Recombinant Proteins, Retinoid X Receptors, Retinoids, Sex Factors, Species Specificity
  • Digital Object Identifier (doi)

    Authorlist

  • Gorman GS; Coward L; Kerstner-Wood C; Cork L; Kapetanovic IM; Brouillette WJ; Muccio DD
  • Start Page

  • 1157
  • End Page

  • 1164
  • Volume

  • 35
  • Issue

  • 7