Characterization of two isomeric β-D-glucosiduronic acids derived from 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in rat liver homogenate incubates

Abstract

Abstract 1,2-Diethyl-3-hydroxypyridin-4-one (CP94) is an orally active iron chelator with potential for use in photodynamic therapy. This investigation reports the formation and characterization of two isomeric glucuronides of CP94 in rat liver homogenate incubates. To assign the glucuronidation sites in the CP94 molecule, two O-methylated derivatives of CP94 have been synthesized. By comparing the spectral characteristics of the CP94 3-O- and 4-O-methyl derivatives with CP94 and the CP94 glucuronides formed during incubation, evidence was obtained which enabled the assignment of these two isomeric glucuronides to the 3-O-glucuronide and 4-O-glucuronide of CP94. It was found that the 3-O-glucuronide was the dominant CP94 metabolite under in-vitro conditions. In an attempt to understand the potential influence of structural variation on the glucuronidation of CP94 analogues, the 1-and 2-monoethyl derivatives of CP94 were investigated. The 2-monoethyl derivative of CP94 yielded only the 3-O-glucuronide in rat liver homogenate incubate, while no glucuronide was formed from the 1-monoethyl derivative. In addition, no glucuronide from the 3-O-methyl or 4-O-methyl derivatives of CP94 could be detected. The relevance of these findings to the development of new 3-hydroxypyridin-4-one iron chelators is discussed.