The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family

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• 作者：Joao N. Dos Santos Pereira (1)
  Sina Tadjerpisheh (1)
  Manar Abu Abed (1)
  Ali R. Saadatmand (1)
  Babette Weksler (2)
  Ignacio A. Romero (3)
  Pierre-Olivier Couraud (4) (5) (6)
  Jürgen Brockm?ller (1)
  Mladen V. Tzvetkov (1)
  
• 关键词：amisulpride ; blood ; brain barrier ; membrane permeability ; organic cation transporters ; sulpiride
• 刊名：The AAPS Journal
• 出版年：2014
• 出版时间：November 2014
• 年：2014
• 卷：16
• 期：6
• 页码：1247-1258
• 全文大小：591 KB
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  11. Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockm?ller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochemical Pharmacology. 2013(0).
  12. Tzvetkov MV, Saadatmand AR, Bokelmann K, Meineke I, Kaiser R, Brockmoller J. Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT3 antagonists tropisetron and ondansetron. Pharmacogenomics J. 2012;12(1):22-. CrossRef
  13. Tzvetkov MV, Saadatmand AR, Lotsch J, Tegeder I, Stingl JC, Brockmoller J. Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther. 2011;90(1):143-0. CrossRef
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  16. Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler
• 作者单位：Joao N. Dos Santos Pereira (1)
  Sina Tadjerpisheh (1)
  Manar Abu Abed (1)
  Ali R. Saadatmand (1)
  Babette Weksler (2)
  Ignacio A. Romero (3)
  Pierre-Olivier Couraud (4) (5) (6)
  Jürgen Brockm?ller (1)
  Mladen V. Tzvetkov (1)
  
  1. Institute for Clinical Pharmacology, University Medical Center G?ttingen, Georg-August University, Robert-Koch-Str. 40, 37075, G?ttingen, Germany
  2. Weill Cornell Medical College, New York, New York, 10065, USA
  3. Department of Life Sciences, The Open University, Walton Hall, Milton Keynes, UK
  4. Inserm, U1016, Institut Cochin, Paris, France
  5. CNRS, UMR8104, Paris, France
  6. Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  
• ISSN：1550-7416

文摘

Variations in influx transport at the blood-brain barrier might affect the concentration of psychotropic drugs at their site of action and as a consequence might alter therapy response. Furthermore, influx transporters in organs such as the gut, liver and kidney may influence absorption, distribution, and elimination. Here, we analyzed 30 commonly used psychotropic drugs using a parallel artificial membrane permeability assay. Amisulpride and sulpiride showed the lowest membrane permeability (P e--.5?×-0??cm/s) and will require influx transport to penetrate the blood-brain barrier and other physiological barriers. We then studied the uptake of amisulpride and sulpiride by the organic cation transporters of the SLC22 family OCT1, OCT2, OCT3, OCTN1, and OCTN2 Amisulpride was found to be transported by all five transporters studied. In contrast, sulpiride was only transported by OCT1 and OCT2. OCT1 showed the highest transport ability both for amisulpride (CLint--.9?ml/min/mg protein) and sulpiride (CLint--.2?ml/min/mg protein) and polymorphisms in OCT1 significantly reduced the uptake of both drugs. Furthermore, we observed carrier-mediated uptake that was inhibitable by known OCT inhibitors in the immortalized human brain microvascular endothelial cell line hCMEC/D3. In conclusion, this study demonstrates that amisulpride and sulpiride are substrates of organic cation transporters of the SLC22 family. SLC22 transporters may play an important role in the distribution of amisulpride and sulpiride, including their ability to penetrate the blood-brain barrier.