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The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1.

Saaby L, Tfelt-Hansen P, Brodin B - Pharmacol Res Perspect (2015)

Bottom Line: Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6.The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4.Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

View Article: PubMed Central - PubMed

Affiliation: Bioneer:FARMA, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark ; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P-glycoprotein (P-gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P-gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P-gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral-to-apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10(-5) cm sec(-1) compared to an apical to basolateral permeability of 1.3 × 10(-5) cm sec(-1). The efflux could be inhibited with the P-gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6. The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

No MeSH data available.


Related in: MedlinePlus

Amount of 3H-digoxin remaining on filter supports including MDCK II (MDR1) cells after an apical to basolateral transport experiment in the presence or absence of telmisartan (2.4 μmol/L). Data were collected from three different passages with three filter support for each treatment and passage (n = 3, N = 3). Bars in the scatter plot designate the mean amount of 3H-digoxin found for each treatment.
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fig06: Amount of 3H-digoxin remaining on filter supports including MDCK II (MDR1) cells after an apical to basolateral transport experiment in the presence or absence of telmisartan (2.4 μmol/L). Data were collected from three different passages with three filter support for each treatment and passage (n = 3, N = 3). Bars in the scatter plot designate the mean amount of 3H-digoxin found for each treatment.

Mentions: The amount of [3H]-digoxin present in cells and filter after a transepithelial transport study in the A-B direction in the absence or presence of 2.4 μmol/L telmarisartan was measured in order to evaluate whether telmisartan affects the cellular uptake of [3H]-digoxin. As shown in Figure6, there were no difference in the amount of [3H]-digoxin present in cells and filter between MDCKII (MDR1) cells incubated in the presence or absence of 2.4 μmol/L telmisartan.


The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1.

Saaby L, Tfelt-Hansen P, Brodin B - Pharmacol Res Perspect (2015)

Amount of 3H-digoxin remaining on filter supports including MDCK II (MDR1) cells after an apical to basolateral transport experiment in the presence or absence of telmisartan (2.4 μmol/L). Data were collected from three different passages with three filter support for each treatment and passage (n = 3, N = 3). Bars in the scatter plot designate the mean amount of 3H-digoxin found for each treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492727&req=5

fig06: Amount of 3H-digoxin remaining on filter supports including MDCK II (MDR1) cells after an apical to basolateral transport experiment in the presence or absence of telmisartan (2.4 μmol/L). Data were collected from three different passages with three filter support for each treatment and passage (n = 3, N = 3). Bars in the scatter plot designate the mean amount of 3H-digoxin found for each treatment.
Mentions: The amount of [3H]-digoxin present in cells and filter after a transepithelial transport study in the A-B direction in the absence or presence of 2.4 μmol/L telmarisartan was measured in order to evaluate whether telmisartan affects the cellular uptake of [3H]-digoxin. As shown in Figure6, there were no difference in the amount of [3H]-digoxin present in cells and filter between MDCKII (MDR1) cells incubated in the presence or absence of 2.4 μmol/L telmisartan.

Bottom Line: Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6.The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4.Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

View Article: PubMed Central - PubMed

Affiliation: Bioneer:FARMA, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup Hospital Glostrup, Denmark ; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark.

ABSTRACT
Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P-glycoprotein (P-gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P-gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P-gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral-to-apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10(-5) cm sec(-1) compared to an apical to basolateral permeability of 1.3 × 10(-5) cm sec(-1). The efflux could be inhibited with the P-gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6-1.6. The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan.

No MeSH data available.


Related in: MedlinePlus