Received for publication December 4, 2006.
Revised April 14, 2007.
Accepted for publication April 16, 2007.

In Vitro Metabolic Characterization, Phenotyping and Kinetic Studies of 9cUAB30, an RXR Specific Retinoid

Abstract

The present study was conducted to compare the in vitro Phase I and Phase II metabolic profiles of 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 a total of 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 human liver microsomes, the specific isozymes responsible for the biotransformations were, CYP2C8, 2C9, 2C19 with minor contributions from CYP1A2 and 2B6. 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, while the remaining four showed evidence of either autoactivation or substrate inhibition.

Key words: cytochrome P450 isoforms, drug development, enzyme kinetics, kinetics, mass spectrometry, metabolite identification, metabolite kinetics, retinoid metabolism, RXR

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