title: A novel prodrug strategy to improve the oral absorption of O-desmethylvenlafaxine.
abstract: O-Desmethylvenlafaxine (desvenlafaxine, ODV) is the active metabolite of venlafaxine, with similar activity and less risk for pharmacokinetic drug interactions compared to its parent compound venlafaxine. The purpose of this study was to design a series of esters of ODV and assess their potential as ODV prodrugs with improved bioavailability and brain uptake. Seven esters were synthesized and pharmacokinetic screening was performed in rats. The monoester formed on the phenolic hydroxyl of ODV (ODVP-1, ODVP-2, ODVP-3 and ODVP-5) could be degraded to ODV in rat plasma. These four compounds confirmed as possible prodrugs were then studied to evaluated the relative bioavailability of ODV they produced in beagle dogs. ODVP-1, ODVP-2 and ODVP-3 demonstrated higher relative bioavailability of ODV. Finally, ODVP-1, ODVP-2 and ODVP-3 were studied to evaluate their brain uptake in rats. The concentration of ODV in the rat plasma, brain and hypothalamus after administration of ODVP-1, ODVP-2 or ODVP-3 was higher compared with that of ODV. The higher bioavailability, improved pharmacokineics properties and more rapid penetration and translation of ODV suggest that ODVP-1, ODVP-2 or ODVP-3 may warrant further development and application as ODV prodrugs.
authors: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China; Department of Pharmacology, College of Basic Medical Sciences, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China.
authors: Mingyuan
authors: M
authors: Liu
authors: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China; School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors: Yantong
authors: Y
authors: Sun
authors: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China.
authors: Sen
authors: S
authors: Zhao
authors: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China.
authors: Youxin
authors: Y
authors: Li
authors: Jilin Institute of Pharmaceutical Research, Changchun, Jilin 130021, P.R. China.
authors: Riyang
authors: R
authors: Piao
authors: National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China; Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors: Yan
authors: Y
authors: Yang
authors: Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun, Jilin 130021, P.R. China.
authors: Jingkai
authors: J
authors: Gu
keywords: O-desmethylvenlafaxine; bioavailability; dog; pharmacokinetics; prodrug; rat