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.