In vitro metabolism of dexamethasone (DEX) in human liver and kidney: The involvement of CYP3a4 and CYP17 (17,20 LYASE) and molecular modelling studies

Abstract

Dexamethasone (DEX) has previously been shown to be extensively metabolised to 6-hydroxylated and side-chain cleaved metabolites in human liver in vitro. CYP3A4 is responsible for 6α- and 6β-hydroxylation of DEX and CYP17 is thought to mediate side-chain cleavage to generate 9αfluoro-androsta-1,4-diene'11β'hydroxy'16α-methyl-3,17-dione (9αF-A). Although 9αF-A has not previously been isolated as a metabolite in its unhydroxylated form in human liver incubations, it is formed as an intermediate metabolite, which is subsequently rapidly hydroxylated to OH-9αF-A. A main part of this study has been to conclusively show that DEX undergoes extensive side-chain cleavage to form 9αF-A in human kidney fractions, which is in contrast to profiles obtained for DEX metabolism in parallel human liver microsomal incubations where 6-hydroxylation is the predominant pathway. Furthermore, molecular models of CYP3A4 and CYP17 (17,20 lyase) have been used to model the enzyme fits of DEX. From these modelling studies it has been shown that DEX complements both putative enzyme active sites in orientations likely to lead to the formation of the metabolites identified in vitro. We have also been able to rationalise the preferential formation of the 6βOH-DEX isomer.