The drug efflux pump P‐glycoprotein (P‐gp) plays an important role in the function of the blood–brain barrier by selectively extruding certain endogenous and exogenous molecules, thus limiting the ability of its substrates to reach the brain. Emerging evidence suggests that P‐gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. Despite some inconsistency in the literature, clinical investigations of potential associations between functional single nucleotide polymorphisms in ABCB1, the gene which encodes P‐gp, and antidepressant response have highlighted a potential link between P‐gp function and treatment‐resistant depression (TRD). Therefore, co‐administration of P‐gp inhibitors with antidepressants to patients who are refractory to antidepressant therapy may represent a novel therapeutic approach in the management of TRD. Furthermore, certain antidepressants inhibit P‐gp in vitro, and it has been hypothesized that inhibition of P‐gp by such antidepressant drugs may play a role in their therapeutic action. The present review summarizes the available in vitro, in vivo and clinical data pertaining to interactions between antidepressant drugs and P‐gp, and discusses the potential relevance of these interactions in the treatment of depression.
Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysisbased pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.
BACKGROUND AND PURPOSERecent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB.
EXPERIMENTAL APPROACHIntracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P-gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals.
KEY RESULTSPretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine.
CONCLUSIONS AND IMPLICATIONSThe present study demonstrated that P-gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P-gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD.
AbbreviationsAUC, area under the concentration-time curve; BBB, blood-brain barrier; C0, initial concentration following bolus intravenous administration; Cl, drug clearance from plasma; CsA, cyclosporin A; ECF, extracellular fluid; HPLC-ECD, high performance liquid chromatography with electrochemical detection; kel, elimination rate constant; PFC, prefrontal cortex; P-gp, P-glycoprotein; PK, pharmacokinetic; SNP, single nucleotide polymorphism; t1/2, half-life of drug in plasma; TRD, treatment-resistant depression; Vd, volume of distribution BJP British Journal of Pharmacology
Although bumetanide reached detectable levels in hippocampal ECF, bumetanide concentration in ECF was low relative to systemic concentration. Oat3 inhibition by probenecid resulted in increased bumetanide concentrations in brain and plasma. As an acute treatment in neonatal seizures, the bumetanide/probenecid combination may hold therapeutic potential.
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