Pharmacological Research 56 (2007) 11–17 Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood–brain barrier Pascale Jolliet a,∗ , St´ ephane Nion b , Gwena¨ elle Allain-Veyrac a , L. Tilloy-Fenart c , Doroth´ ee Vanuxeem c , Vincent Berezowski c , Rom´ eo Cecchelli c a Laboratoire de Pharmacologie, Facult´ e de M´ edecine, 1, Rue Gaston Veil, 44305 Nantes Cedex 01, France b CELLIAL Technologies, Facult´ e Jean Perrin, Rue Jean Souvraz, Lens, France c Laboratoire de Physiopathologie de la Barri` ere H´ emato Enc´ ephalique, Universit´ e d’Artois, Facult´ e Jean Perrin, Rue Jean Souvraz, Lens, France Accepted 7 December 2006 Abstract Purpose: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood–brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). Methods: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. Results: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. Conclusions: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile. © 2007 Published by Elsevier Ltd. Keywords: Metopimazine; Antiemetic; Blood–brain barrier; Drug delivery; In vitro model 1. Introduction The antiemetic chemical structure (domperidone, metoclo- pramide, metopimazine and chlorpromazine) are relatively close to the neuroleptic drugs. This chemical similarity could lead to confusion about the pharmacological properties of these com- pounds. Domperidone is a peripheral dopaminergic antagonist and metoclopramide central and peripheral one. The objective of the current study was to determine the ability of these four compounds and also metopimazine acid to cross the blood–brain barrier (BBB). Metopimazine acid is the active in vivo metabolite obtained from metopimazine. Up to now, the cerebral perme- Abbreviations: BBB, blood–brain barrier; BCEC, brain capillary endothelial cell; CNS, central nervous system; EC, endothelial cell; HEPES, N-[2-hydroxy- ethyl]piperazine-N ′ -2[2-ethanesulfonic acid]; HPLC, high-performance liquid chromatography; Pe, permeability coefficient of endothelial cells ∗ Corresponding author. Tel.: +33 2 40 41 28 57; fax: +33 2 40 08 40 97. E-mail address: pascale.jolliet@univ-nantes.fr (P. Jolliet). ability of these compounds were obtained only by indirect observations. The BBB is situated at the cerebral capillary endothelium and represents the principal route for the entry into the central nervous system (CNS). Due to the presence of this restrictive barrier between the blood and the brain, BBB drug delivery strategy must be considered. To overcome the limitations of in vivo studies, many lab- oratories turned to in vitro techniques for determining BBB permeability of potential drug candidates. In this study, we used a co-culture model of brain capillary endothelial cells and glial cells for mimicking the BBB. With this in vitro co-culture model, we obtain permeability values which allow us to com- pare the compounds, considering their ability to cross the BBB and thereby, to determine possible side effects of compounds for the CNS. Many agents are used for treatment of nausea and vomit- ing including 5-HT3 antagonists and dopamine D2 antagonists (substituted benzamides, phenothiazines, and benzimidazole derivatives). 5-HT3 antagonists (ondansetron, granisetron, 1043-6618/$ – see front matter © 2007 Published by Elsevier Ltd. doi:10.1016/j.phrs.2006.12.004