A Phenolic Ester of O-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

In this study, the in vitro stabilities of a promising O-Desmethylvenlafaxine (ODV) phenolic ester prodrug O-19 in aqueous solution, rat whole blood and rat liver microsomes were investigated. In addition, the in vivo drug metabolites were determined using LC-TOFMS-IDA-MS/MS. O-19 exhibits high stabilities at any pH encountered in the gastrointestinal tract, its half live (t_1/2) spans the range 5.0±0.18 d ~ 686±29.5 d. However, O-19 experiences rapid enzymatic hydrolysis in rat whole blood (t_1/2 = 3.6±0.53 min) and rat liver microsomes (t_1/2 = 9.5±1.53 min). The metabolic profile of O-19 is similar to that of ODV. Besides ODV itself, five metabolites are identified in rat urine (M₁~M₅) and faeces (M₁, M₄), no obvious toxic metabolite is detected.