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Published online: 21 August 2015
© Springer International Publishing Switzerland 2015
Abstract As the effect of P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an increasing number of publications have addressed the effect of P-gp in limiting brain penetration of antidepressants and causing treatment-resistant depression in current clinical therapies. However, contradictory results have been observed in different systems. It is of vital importance to understand the potential for drug interactions related to P-gp at the blood-brain barrier (BBB), and whether coadministration of a P-gp inhibitor together with an antidepressant is a good clinical strategy for dosing of patients with treatment-resistant depression. In this review, the complicated construction of the BBB, the transport mechanisms for compounds that cross the BBB, and the basic characteristics of antidepressants are illustrated. Further, the reliability of different systems related to antidepressant brain delivery, including in vitro bidirectional transport cell lines, in vivo Mdr1 knockout mice, and chemical inhibition studies in rodents are analyzed, supporting a low possibility that P-gp affects currently marketed antidepressants when these results are extrapolated to the human BBB. These findings can also be applied to other central nervous system drugs.
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1 Background
Depression is currently the fourth most serious global health problem, especially in the developed world [1]. Most antidepressants used in the clinic are small, lipophilic molecules that can readily cross endothelial cells via passive diffusion [2]. For a long time, passive diffusion has been viewed as a major mechanism for good penetration of antidepressants at the blood-brain barrier (BBB). In the last 20 years, with the availability of the P-glycoprotein (P-gp) knockout mouse model, numerous studies have been conducted in P-gp knockout versus wild-type mice and significant P-gp efflux of antidepressants has been observed, followed by an increasing number of publications that address the important role of P-gp expressed at the brain capillary endothelial cells on the efflux of most antidepressants at the BBB [3]. Thus, efflux of antidepressants by brain P-gp has been regarded as one important factor that potentially results in treatment-resistant depression [4].Aseries of studies in rodents with chemical inhibition of P-gp were conducted based on the observation in the knockout model. However,...