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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

(A) Transepithelial transport of [3H]-digoxin (0.03 μmol/L) across MDCK II (MDR1) cells as a function of time, in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of digoxin on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 3, N = 3). (B) The apparent transepithelial permeability of [3H]-digoxin (0.03 μmol/L) in the apical to basolateral (grey bars) and basolateral to apical (white bars) direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data represent the means ± SD (n = 3, N = 3).
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fig05: (A) Transepithelial transport of [3H]-digoxin (0.03 μmol/L) across MDCK II (MDR1) cells as a function of time, in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of digoxin on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 3, N = 3). (B) The apparent transepithelial permeability of [3H]-digoxin (0.03 μmol/L) in the apical to basolateral (grey bars) and basolateral to apical (white bars) direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data represent the means ± SD (n = 3, N = 3).

Mentions: In order to investigate if a possible inhibitory effect of telmisartan would be more readily detectable when using a P-gp substrate with a higher PB-A/PA-B than verapamil, the bidirectional transport of the well-known P-gp substrate [3H]-digoxin across MDCK II (MDR1) cells and the cellular accumulation was measured (Fig.5A). The flux of [3H]-digoxin was constant over the entire time course of the experiments in both the A-B and the B-A direction with an estimated A-B permeability of 1.4 ± 0.2 × 10−6 cm sec−1 (n = 3, N = 3), while the permeability was estimated to be 1.5 ± 0.1 × 10−5 cm sec−1 (n = 3, N = 3) in the B-A direction (Fig.5B). The corresponding efflux ratio was 10.7 in favor of the B-A direction, which indicated a net efflux of [3H]-digoxin across the MDCK II (MDR1) cell monolayers. In the presence of 2.4 μmol/L telmisartan, the A-B and the B-A permeability of [3H]-digoxin was estimated to be 1.5 ± 0.3 × 10−6 cm sec−1 and 1.7 ± 0.1 × 10−5 cm sec−1 (n = 3, N = 3), respectively (Fig.5B). The resulting efflux ratio of [3H]-digoxin was 11.2 favor of the B-A direction, which indicates an active efflux of [3H]-digoxin in the presence of 2.4 μmol/L telmisartan. In the same experiments, the efflux ratio of the paracellular flux marker [14C]-mannitol was 1.1.


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)

(A) Transepithelial transport of [3H]-digoxin (0.03 μmol/L) across MDCK II (MDR1) cells as a function of time, in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of digoxin on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 3, N = 3). (B) The apparent transepithelial permeability of [3H]-digoxin (0.03 μmol/L) in the apical to basolateral (grey bars) and basolateral to apical (white bars) direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data represent the means ± SD (n = 3, N = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492727&req=5

fig05: (A) Transepithelial transport of [3H]-digoxin (0.03 μmol/L) across MDCK II (MDR1) cells as a function of time, in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of digoxin on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 3, N = 3). (B) The apparent transepithelial permeability of [3H]-digoxin (0.03 μmol/L) in the apical to basolateral (grey bars) and basolateral to apical (white bars) direction across MDCK II (MDR1) cells in the presence or absence of telmisartan (TEL, 2.4 μmol/L). Data represent the means ± SD (n = 3, N = 3).
Mentions: In order to investigate if a possible inhibitory effect of telmisartan would be more readily detectable when using a P-gp substrate with a higher PB-A/PA-B than verapamil, the bidirectional transport of the well-known P-gp substrate [3H]-digoxin across MDCK II (MDR1) cells and the cellular accumulation was measured (Fig.5A). The flux of [3H]-digoxin was constant over the entire time course of the experiments in both the A-B and the B-A direction with an estimated A-B permeability of 1.4 ± 0.2 × 10−6 cm sec−1 (n = 3, N = 3), while the permeability was estimated to be 1.5 ± 0.1 × 10−5 cm sec−1 (n = 3, N = 3) in the B-A direction (Fig.5B). The corresponding efflux ratio was 10.7 in favor of the B-A direction, which indicated a net efflux of [3H]-digoxin across the MDCK II (MDR1) cell monolayers. In the presence of 2.4 μmol/L telmisartan, the A-B and the B-A permeability of [3H]-digoxin was estimated to be 1.5 ± 0.3 × 10−6 cm sec−1 and 1.7 ± 0.1 × 10−5 cm sec−1 (n = 3, N = 3), respectively (Fig.5B). The resulting efflux ratio of [3H]-digoxin was 11.2 favor of the B-A direction, which indicates an active efflux of [3H]-digoxin in the presence of 2.4 μmol/L telmisartan. In the same experiments, the efflux ratio of the paracellular flux marker [14C]-mannitol was 1.1.

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