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


METHODS
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.


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
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.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Yan
Y
Sun
Jieyu
J
Dai
Zheyi
Z
Hu
Feifei
F
Du
Wei
W
Niu
Fengqing
F
Wang
Fei
F
Liu
Guozhang
G
Jin
Chuan
C
Li
D000284:Administration, Oral; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003600:Cytosol / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D013045:Species Specificity; D013237:Stereoisomerism; D014020:Tissue Extracts / Q000378:metabolism
D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D014020:Tissue Extracts; D001599:Berberine; C010513:stepholidine