title: Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain.
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.
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 533 Parnassus Avenue, Room U-68, San Francisco, CA, 94143-0912, USA.|Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors: Yi
authors: Y
authors: Zheng
authors: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors: Xijing
authors: X
authors: Chen
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 533 Parnassus Avenue, Room U-68, San Francisco, CA, 94143-0912, USA. leslie.benet@ucsf.edu.
authors: Leslie Z
authors: LZ
authors: Benet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D006801:Humans
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents