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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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Related in: MedlinePlus

Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with increasing doses of sertraline (SERT) and 10−4 of verapamil (VPL).Calcein accumulation was assessed at (A) 15 min, (B) 60 min, (C), 120 min and (D) 240 min. * indicates p<0.05 and ** indicates p<0.01 compared to control cells.
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pone-0056525-g001: Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with increasing doses of sertraline (SERT) and 10−4 of verapamil (VPL).Calcein accumulation was assessed at (A) 15 min, (B) 60 min, (C), 120 min and (D) 240 min. * indicates p<0.05 and ** indicates p<0.01 compared to control cells.

Mentions: All data are presented as the percentage of the fluorescent calcein accumulation in untreated control cells. Therefore, an increase in relative calcein accumulation represents inhibition of P-gp function. There was no significant increase in calcein accumulation at 15 minutes with sertraline treatment (Fig. 1A). At 60 minutes, sertraline treatment (10−5 M) resulted in an 86% increase in calcein accumulation compared to control cells (p<0.05; Fig. 1B). By 120 minutes, all doses of sertraline resulted in significant inhibition of P-gp function – peaking at a 135% increase in calcein accumulation in cells treated with 10−5 M sertraline (p<0.01; Fig. 1C). Likewise at 240 minutes, all doses of sertraline displayed significant inhibition of P-gp function (P<0.05; Fig. 1D).


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 increasing doses of sertraline (SERT) and 10−4 of verapamil (VPL).Calcein accumulation was assessed at (A) 15 min, (B) 60 min, (C), 120 min and (D) 240 min. * indicates p<0.05 and ** indicates p<0.01 compared to control cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056525-g001: Calcein accumulation in guinea pig primary brain endothelial cells (n = 6) presented as % of control with increasing doses of sertraline (SERT) and 10−4 of verapamil (VPL).Calcein accumulation was assessed at (A) 15 min, (B) 60 min, (C), 120 min and (D) 240 min. * indicates p<0.05 and ** indicates p<0.01 compared to control cells.
Mentions: All data are presented as the percentage of the fluorescent calcein accumulation in untreated control cells. Therefore, an increase in relative calcein accumulation represents inhibition of P-gp function. There was no significant increase in calcein accumulation at 15 minutes with sertraline treatment (Fig. 1A). At 60 minutes, sertraline treatment (10−5 M) resulted in an 86% increase in calcein accumulation compared to control cells (p<0.05; Fig. 1B). By 120 minutes, all doses of sertraline resulted in significant inhibition of P-gp function – peaking at a 135% increase in calcein accumulation in cells treated with 10−5 M sertraline (p<0.01; Fig. 1C). Likewise at 240 minutes, all doses of sertraline displayed significant inhibition of P-gp function (P<0.05; Fig. 1D).

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