ABSTRACT
This investigation includes an evaluation of the percutaneous absorption of bupropion (BUP) and hydroxybupropion (BUPOH) in vitro and in vivo. In addition, a carbamate prodrug of BUPOH (But-BUPOH) was evaluated in vitro. In vitro diffusion studies were conducted in a flow-through diffusion cell system. The in vitro mean steady-state flux of BUP was significantly higher (p < 0.001) compared to BUPOH (320 +/- 16 nmol cm(-2) h(-1) vs. 27 +/- 4 nmol cm(-2) h(-1)). Additionally, a good correlation existed between in vitro and in vivo results. Mean steady-state plasma concentrations of 442 +/- 32 ng/mL and125 +/- 18 ng/mL were maintained over 48 h after topical application of BUP and BUPOH in hairless guinea pigs in vivo, respectively. Although BUP traversed human skin at rates sufficient to achieve required plasma levels, it is chemically unstable and hygroscopic, and unsuitable for transdermal formulation. On the other hand, BUPOH is stable but its transport across skin is much slower. Alternatively, the prodrug But-BUPOH was found to be stable, and also provided a 2.7-fold increase in the transdermal flux of BUPOH across human skin in vitro. Thus, But-BUPOH provides a viable option for the transdermal delivery of BUPOH.
Subject(s)
Bupropion/analogs & derivatives , Carbamates/administration & dosage , Dopamine Uptake Inhibitors/administration & dosage , Prodrugs/administration & dosage , Skin Absorption , Skin/metabolism , Administration, Cutaneous , Animals , Bupropion/administration & dosage , Bupropion/blood , Bupropion/chemistry , Bupropion/pharmacokinetics , Carbamates/blood , Carbamates/chemistry , Carbamates/pharmacokinetics , Diffusion , Diffusion Chambers, Culture , Dopamine Uptake Inhibitors/blood , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacokinetics , Drug Stability , Female , Guinea Pigs , Humans , Hydrogen-Ion Concentration , Male , Models, Biological , Prodrugs/chemistry , Prodrugs/pharmacokinetics , SolubilityABSTRACT
Based on the earlier results of our in-house database and compound library, a series of novel clubbed thienyl triazoles was designed which may emerge as potential cdk5/p25 inhibitors, for the treatment of Alzheimer's disease. A benign synthesis was planned so as to take an advantage of MAOS (Microwave Assisted Organic Synthesis) method. Evaluation of the SAR of this series has allowed the identification of compounds 4, 5, 7 and 8 from series I while 13, 14, 16 and 17 from series II as significant cdk5/p25 inhibitors and thus have potential as possible treatments for Alzheimer's disease.
