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Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches.

Kapoor A, Iqbal M, Petropoulos S, Ho HL, Gibb W, Matthews SG - PLoS ONE (2013)

Bottom Line: In vivo, a biphasic effect was demonstrated.Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control.There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.

View Article: PubMed Central - PubMed

Affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA. akapoor@wisc.edu

ABSTRACT

Background and purpose: Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.

Experimental approach: The P-gp substrate, tritiated digoxin ([(3)H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.

Key results: In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.

Conclusions and implications: Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.

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Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with 10−5 dose of sertraline (SERT), fluoxetine (FLX) and 10−4 of verapamil (VPL) assessed at 60 min.* indicates p<0.05 compared to control cells.
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pone-0056525-g002: Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with 10−5 dose of sertraline (SERT), fluoxetine (FLX) and 10−4 of verapamil (VPL) assessed at 60 min.* indicates p<0.05 compared to control cells.

Mentions: Levels of inhibition caused by sertraline treatment were comparable to the inhibition induced by treatment with the commonly used P-gp inhibitor, verapamil (Fig. 2). P-gp inhibition by verapamil (10−4 M) followed a similar profile to that observed with sertraline (10−5 M). Treatment of cells with fluoxetine (10−5 M) resulted in no inhibition of P-gp at any of the time points tested (Fig. 2). Higher doses of sertraline and fluoxetine (10−3 & 10−4), and verapamil (10−3) resulted in significant cell death (>90%; data not shown) as determined by Trypan blue staining.


Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches.

Kapoor A, Iqbal M, Petropoulos S, Ho HL, Gibb W, Matthews SG - PLoS ONE (2013)

Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with 10−5 dose of sertraline (SERT), fluoxetine (FLX) and 10−4 of verapamil (VPL) assessed at 60 min.* indicates p<0.05 compared to control cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585317&req=5

pone-0056525-g002: Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with 10−5 dose of sertraline (SERT), fluoxetine (FLX) and 10−4 of verapamil (VPL) assessed at 60 min.* indicates p<0.05 compared to control cells.
Mentions: Levels of inhibition caused by sertraline treatment were comparable to the inhibition induced by treatment with the commonly used P-gp inhibitor, verapamil (Fig. 2). P-gp inhibition by verapamil (10−4 M) followed a similar profile to that observed with sertraline (10−5 M). Treatment of cells with fluoxetine (10−5 M) resulted in no inhibition of P-gp at any of the time points tested (Fig. 2). Higher doses of sertraline and fluoxetine (10−3 & 10−4), and verapamil (10−3) resulted in significant cell death (>90%; data not shown) as determined by Trypan blue staining.

Bottom Line: In vivo, a biphasic effect was demonstrated.Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control.There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.

View Article: PubMed Central - PubMed

Affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA. akapoor@wisc.edu

ABSTRACT

Background and purpose: Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.

Experimental approach: The P-gp substrate, tritiated digoxin ([(3)H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.

Key results: In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.

Conclusions and implications: Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.

Show MeSH
Related in: MedlinePlus