title: The poorly membrane permeable antipsychotic drugs amisulpride and sulpiride are substrates of the organic cation transporters from the SLC22 family.
abstract: 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 < 1.5 × 10(-6) 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 = 1.9 ml/min/mg protein) and sulpiride (CLint = 4.2 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.
authors.affiliation: Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
authors.forename: Joao N
authors.initials: JN
authors.lastname: Dos Santos Pereira
authors.forename: Sina
authors.initials: S
authors.lastname: Tadjerpisheh
authors.forename: Manar
authors.initials: M
authors.lastname: Abu Abed
authors.forename: Ali R
authors.initials: AR
authors.lastname: Saadatmand
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Mladen V
authors.initials: MV
authors.lastname: Tzvetkov
mesh_terms: D000077582:Amisulpride; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008567:Membranes, Artificial; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D008567:Membranes, Artificial; D027701:Organic Cation Transport Proteins; D013469:Sulpiride; D000077582:Amisulpride