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Abstract
1. Control and P4502D6-transfected human B-lymphoblastoid cell lines (cHol and h2D6v2 respectively) were used to study 2D6-mediated metabolism of methoxyphenamine (MPA) and 2-methoxyamphetamine (2MA). The main metabolites were products of O-dealkylation and aromatic hydroxylation at the 5-position. In addition, N-desmethyl-methoxyphenamine (NDMP) was also identified as a minor metabolite of MPA in extracts of these cells, confirming previous reports of 2D6-mediated N-demethylation of MPA.
2. An additional ring-hydroxylated metabolite of MPA and 2MA has been tentatively identified as the corresponding 3-hydroxy-2-methoxy derivative.
3. MPA metabolism in whole cells was time dependent, with approximately 30% of the MPA metabolized after 72h. A 35% conversion of MPA was achieved on average with cell lysates. Only 18% 2MA was metabolized. By contrast, control cells (cHol) showed no evidence of any MPA or 2MA metabolites even after 96-h incubation.
4. Continuous presence of haemin/dimethylsulphoxide (DMSO) throughout the 4-day incubation with MPA resulted in a shift in the metabolite profile towards the production of NDMP at the expense of the other products.
5. In summary, h2D6v2 cells, lysates and microsomes can form all metabolites of MPA and can be used in drug interaction studies.