Oral bioavailability and brain penetration of (−)‐stepholidine, a tetrahydroprotoberberine agonist at dopamine D₁ and antagonist at D₂ receptors, in rats

BACKGROUND AND PURPOSE: (-)-Stepholidine has high affinity for dopamine D(1) and D(2) 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 approximately 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.