Brain penetration is characterized by its extent and rate and is influenced by drug physicochemical properties, plasma exposure, plasma and brain protein binding and BBB permeability. This raises questions related to physiology, interspecies differences and in vitro/in vivo extrapolation. We herein discuss the use of in vitro human and animal BBB model as a tool to improve CNS compound selection. These cell-based BBB models are characterized by low paracellular permeation, well-developed tight junctions and functional efflux transporters. A study of twenty drugs shows similar compound ranking between rat and human models although with a 2-fold higher permeability in rat. cLogP < 5, PSA < 120 Å, MW < 450 were confirmed as essential for CNS drugs. An in vitro/in vivo correlation in rat (R² = 0.67; P = 2 × 10⁻⁴) was highlighted when in vitro permeability and efflux were considered together with plasma exposure and free fraction. The cell-based BBB model is suitable to optimize CNS-drug selection, to study interspecies differences and then to support human brain exposure prediction.

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In the present study, norepinephrine (NE), epinephrine (E), dopamine (DA) and 5-hydroxy-tryptamine (5HT) have been quantified by high performance liquid chromatography (HPLC) in Pecten maximus during larval and post-larval development. With average values ranging from 2 to 5 pg µg -1 of protein, NE remained low through the whole larval life, while epinephrine (E) was undetected. DA and 5HT were the most abundant monoamines with significant variations between larval, pre-metamorphic and post-larval stages. During the first 20 days, corresponding to D larval and umboned larval stages, levels of DA and 5HT increased from 15 to 30 and 10 to 15 pg µg -1 of protein, respectively. Then during the last week of larval life, at the approach of metamorphosis, DA rose sharply from 30 to 50 pg µg -1 of protein and 5HT from 15 to 50 pg µg -1 of protein. Lastly during the first week of post-larval life (day 27 to day 34) DA and 5HT contents declined to levels similar to those detected in the first days of larval life reaching progressively 1 pg µg -1 of protein during the second week of post-larval life (day 34 to day 55). These rapid and transient variations in monoamine contents (5HT and DA) around metamorphosis, present a great interest. However, this relation between neurochemical changes and metamorphosis must be confirmed with future studies in order to verify if such monoamines might be used as indicators of larval competence in P. maximus, a commercially important species. Résumé Évolution ontogénique des teneurs en dopamine, adrénaline et sérotonine chez les larves et post-larves du bivalve Pecten maximus.L'évolution des teneurs en noradrénaline, adrénaline, dopamine et sérotonine a été étudiée en phase larvaire et post-larvaire chez la coquille St-Jacques Pecten maximus. Avec des valeurs moyennes (déterminées par HPLC) comprises entre 2 et 5 pg µg -1 de protéine, la noradrénaline fluctue peu tandis que l'adrénaline n'a pu être détectée quel que soit le stade considéré, larvaire ou post-larvaire. La dopamine et la sérotonine étaient particulièrement abondantes et présentaient des variations significatives entre les phases larvaire, pré-métamorphique et post-larvaire. Au cours des 20 premiers jours, correspondant aux stades larves D puis umbonées, les teneurs en dopamine et sérotonine augmentent progressivement de 15 à 30 pg µg -1 et de 10 à 15 pg µg -1 respectivement. Puis, au cours de la dernière semaine de vie larvaire, à l'approche de la métamorphose, la teneur en dopamine augmente brusquement de 30 à 50 pg µg -1 et celle de la sérotonine de 15 à 50 pg µg -1 . Enfin, durant la métamorphose et la première semaine de vie post-larvaire (jours 27 à 34) les concentrations en dopamine et sérotonine chutent jusqu'à des valeurs similaires à celles détectées en début de vie larvaire et atteignent, au cours de la deuxième semaine (jours 34 à 55), des valeurs proches de 1 pg µg -1 . Ces brusques variations des contenus en dopamine et sérotonine autour de la métamorphose présentent un réel intérêt. Cependant, cette relation ent...

Bivalve metamorphosis is defined by anatomical, morphological and physiological transformation. Despite its importance, few studies have been devoted to this critical phase of Pectinidae (Cragg and Crisp, 1991). The development of reliable hatchery technology (Loosanoff and Davis, 1963) allowed a better knowledge of this phase, with the first research focusing mainly on describing organogenesis (Sastry, 1965). Since 1985, the role of chemical cues has been investigated. Its influence on metamorphosis has been studied in detail in Pacific oysters, Crassostrea gigas (Coon et al., 1985) and C. virginica (Coon et al., 1986) and in the European oyster Ostrea edulis (Shpigel et al., 1989). However, for Pectinidae these kinds of data are sparse (Kingzett et al., 1990;Chevolot et al., 1991). Nevertheless, during metamorphosis, the process of fixation differs greatly between Pectinidae and Ostreidae, the latter being characterized by cementation during settlement. Consequently, the chemical cues involved and the control pathway could be different.Some experiments have suggested enhancement of bivalve setting by physical factors; the role of these sensory inputs in oyster metamorphosis has been schematized by Bonar et al. (1990). Shpigel et al. (1989) have shown that exposure of O. edulis larvae to either epinephrine or shell chips alone resulted in similar rates of metamorphosis. Consequently, the relative importance of the two types of cues, chemical and physical, needs to be clarified. Such a study has been carried out at the experimental mollusc hatchery of Argenton (Britanny, France), C. gigas and the great scallop (Pecten maximus) being the two biological models used. The purpose of this research was to develop a reliable method to enhance the rate of metamorphosis of the great scallop.The effect of epinephrine, abundantly described in the oyster, and the influence of seawater flow rate, which seems to be of great importance for the Pectinidae