Background and purpose:  (−)-Stepholidine has high affinity for dopamine D₁ and D₂ receptors. The aims of the present study were to examine the oral bioavailability and brain penetration of (−)-stepholidine and to gain understanding of mechanisms governing its transport across the enterohepatic barrier and the blood–brain barrier.

Experimental approach:  The pharmacokinetics of (−)-stepholidine was studied in rats and microdialysis was used to measure delivery to the brain. These studies were supported by biological measurement of unbound (−)-stepholidine. Membrane permeability was assessed using Caco-2 cell monolayers. Metabolite profiling of (−)-stepholidine in rat bile and plasma was performed. Finally, in vitro metabolic stability and metabolite profile of (−)-stepholidine were examined to compare species similarities and differences between rats and humans.

Key results:  Orally administered (−)-stepholidine was rapidly absorbed from the gastrointestinal tract; two plasma concentration peaks were seen, and the second peak might result from enterohepatic circulation. Due to extensive pre-systemic metabolism, the oral bioavailability of (−)-stepholidine was poor (<2%). However, the compound was extensively transported across the blood–brain barrier, demonstrating an AUC (area under concentration–time curve) ratio of brain : plasma of ∼0.7. (−)-Stepholidine showed good membrane permeability that was unaffected by P-glycoprotein and multidrug resistance-associated protein 2. In vitro (−)-stepholidine was metabolized predominantly by glucuronidation and sulphation in rats and humans, but oxidation of this substrate was very low.

Conclusions and implications:  Although (−)-stepholidine exhibits good brain penetration, future development efforts should aim at improving its oral bioavailability by protecting against pre-systemic glucuronidation or sulphation. In this regard, prodrug approaches may be useful.