Details

Autor(en) / Beteiligte

• Sun, Yan
• Dai, Jieyu
• Hu, Zheyi
• Du, Feifei
• Niu, Wei
• Wang, Fengqing
• Liu, Fei
• Jin, Guozhang
• Li, Chuan

Titel

Oral bioavailability and brain penetration of (−)‐stepholidine, a tetrahydroprotoberberine agonist at dopamine D 1 and antagonist at D 2 receptors, in rats

Ist Teil von

• British journal of pharmacology, 2009-11, Vol.158 (5), p.1302-1312

Erscheinungsjahr

2009

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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 ∼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.