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Synthesis, Screening and Pharmacokinetic Evaluation of Potential Prodrugs of Bupropion. Part One: In Vitro Development
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Pharmaceuticals 2014, 7(6), 676-694;

Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug

School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College, Dublin 9, Ireland
Author to whom correspondence should be addressed.
Received: 13 March 2014 / Revised: 15 May 2014 / Accepted: 19 May 2014 / Published: 28 May 2014
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans. View Full-Text
Keywords: N-methylbupropion; bupropion; bioprecursor; prodrug; microsomes; plasma; in vivo; metabolism N-methylbupropion; bupropion; bioprecursor; prodrug; microsomes; plasma; in vivo; metabolism

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O'Byrne, P.M.; williams, R.; walsh, J.J.; Gilmer, J.F. Part Two: Evaluation of N-methylbupropion as a Potential Bupropion Prodrug. Pharmaceuticals 2014, 7, 676-694.

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