Limits...
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

Transepithelial transport of [3H]-verapamil (12 μmol/L) across MDCK II (MDR1) in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of verapamil on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 9, N = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492727&req=5

fig01: Transepithelial transport of [3H]-verapamil (12 μmol/L) across MDCK II (MDR1) in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of verapamil on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 9, N = 3).

Mentions: The transepithelial transport of [3H]-verapamil across MDCK II (MDR1) cell monolayers was measured in both the A-B and the B-A direction. The flux of [3H]-verapamil was higher in the B-A direction than the flux in the A-B direction, indicating a vectorial net transport of the compound in the B-A direction (Fig.1). The flux of [3H]-verapamil was not constant over the entire time course of the experiments. This was especially pronounced for the B-A fluxes (Fig.1). The observed time-dependent change in fluxes was probably caused by a change in the concentration gradient of [3H]-verapamil across the MDCK II (MDR1) cells, which, in turn, is caused by a high initial transport rate. Fluxes, for calculation of permeabilities, were therefore extrapolated from the linear part of the accumulation curves, as described in methods. The A-B permeability of [3H]-verapamil was estimated to be 1.3 ± 0.2 × 10−5 cm sec−1 (n = 15, N = 3) which was significantly lower (P < 0.0001) than the permeability in the B-A direction of 5.5 ± 0.8 × 10−5 cm sec−1 (n = 15, N = 3). The efflux ratio PB-A/PA-B was 4.4. In comparison, the efflux ratio of the paracellular flux marker [14C]-mannitol was ∼1.5. Ideally this efflux ratio will be 1 if no net transport occurs, however, in practice the B-A flux of mannitol may be slightly larger than the A-B flux in the presence of agonists and their solvents, probably due to a slight interference with tight junctions. The small increase in paracellular permeability is not likely to influence the larger transcellular efflux of verapamil.


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)

Transepithelial transport of [3H]-verapamil (12 μmol/L) across MDCK II (MDR1) in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of verapamil on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 9, N = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Transepithelial transport of [3H]-verapamil (12 μmol/L) across MDCK II (MDR1) in the apical to basolateral (closed circles) and the basolateral to apical direction (closed squares). Data show accumulation of verapamil on the acceptor side as a function of time. Data points represent the means, while error bars designate the standard deviations (n = 9, N = 3).
Mentions: The transepithelial transport of [3H]-verapamil across MDCK II (MDR1) cell monolayers was measured in both the A-B and the B-A direction. The flux of [3H]-verapamil was higher in the B-A direction than the flux in the A-B direction, indicating a vectorial net transport of the compound in the B-A direction (Fig.1). The flux of [3H]-verapamil was not constant over the entire time course of the experiments. This was especially pronounced for the B-A fluxes (Fig.1). The observed time-dependent change in fluxes was probably caused by a change in the concentration gradient of [3H]-verapamil across the MDCK II (MDR1) cells, which, in turn, is caused by a high initial transport rate. Fluxes, for calculation of permeabilities, were therefore extrapolated from the linear part of the accumulation curves, as described in methods. The A-B permeability of [3H]-verapamil was estimated to be 1.3 ± 0.2 × 10−5 cm sec−1 (n = 15, N = 3) which was significantly lower (P < 0.0001) than the permeability in the B-A direction of 5.5 ± 0.8 × 10−5 cm sec−1 (n = 15, N = 3). The efflux ratio PB-A/PA-B was 4.4. In comparison, the efflux ratio of the paracellular flux marker [14C]-mannitol was ∼1.5. Ideally this efflux ratio will be 1 if no net transport occurs, however, in practice the B-A flux of mannitol may be slightly larger than the A-B flux in the presence of agonists and their solvents, probably due to a slight interference with tight junctions. The small increase in paracellular permeability is not likely to influence the larger transcellular efflux of verapamil.

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