Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D-1 and antagonist at D-2 receptors, in rats
文献类型：期刊论文
| 作者 | Sun, Yan; Dai, Jieyu; Hu, Zheyi; Du, Feifei; Niu, Wei; Wang, Fengqing; Liu, Fei; Jin, Guozhang ; Li, Chuan
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| 刊名 | BRITISH JOURNAL OF PHARMACOLOGY
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| 出版日期 | 2009-11 |
| 卷号 | 158期号:5页码:1302-1312 |
| 关键词 | (-)-stepholidine CNS drug enterohepatic barrier blood-brain barrier oral bioavailability brain penetration metabolic profiling prodrug |
| ISSN号 | 0007-1188 |
| DOI | 10.1111/j.1476-5381.2009.00393.x |
| 文献子类 | Article |
| 英文摘要 | 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 similar to 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. |
| WOS关键词 | L-STEPHOLIDINE ; CLINICAL-IMPLICATIONS ; MASS-SPECTROMETRY ; DRUG-METABOLISM ; SCHIZOPHRENIA ; PLASMA ; QUANTIFICATION ; HUMANS ; D1 |
| 资助项目 | Chinese Ministry of Science and Technology[2004CB720305] ; Chinese Ministry of Science and Technology[2005CB523403] ; National Natural Science Foundation of China[30213204] ; National Natural Science Foundation of China[30873120] ; Science & Technology Commission of Shanghai Municipality[04DZ19215] ; SIMM-CAS[07G603J049] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000271001400012 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279091]  |
| 专题 | 上海药物代谢研究中心 科研与新药推进处 |
| 通讯作者 | Li, Chuan |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, SIBS, Shanghai Ctr DMPK Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Yan,Dai, Jieyu,Hu, Zheyi,et al. Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D-1 and antagonist at D-2 receptors, in rats[J]. BRITISH JOURNAL OF PHARMACOLOGY,2009,158(5):1302-1312. |
| APA | Sun, Yan.,Dai, Jieyu.,Hu, Zheyi.,Du, Feifei.,Niu, Wei.,...&Li, Chuan.(2009).Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D-1 and antagonist at D-2 receptors, in rats.BRITISH JOURNAL OF PHARMACOLOGY,158(5),1302-1312. |
| MLA | Sun, Yan,et al."Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D-1 and antagonist at D-2 receptors, in rats".BRITISH JOURNAL OF PHARMACOLOGY 158.5(2009):1302-1312. |
入库方式： OAI收割
来源：上海药物研究所
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