Reversal of Multidrug Resistance by R-Verapamil

Schumacher, K.; Ladda, E.; Bühl, K.; Weimer, Abram; Eser, C.; Traugott, U.; Roller, E.; Löffler, Birgit; Eichelbaum, Michel

doi:10.1007/978-3-642-78350-0_42

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“…Thus, total in vivo plasma concentrations in the order of 20-40 Ìmol/l correspond to the 2-4 Ìmol/l used in this study. However, with the high doses of R verapamil employed in this clinical phase I study, 400-2,400 mg/day, plasma concentrations of verapamil and norverapamil as high as 20-25 Ìmol/l were achieved [8].…”

Section: Discussionmentioning

confidence: 99%

“…Because of its much lesser cardiovascular activity, R verapamil can be administered at much higher concentrations. In a phase I clinical trial in which doses between 400 and 2,400 mg/day of R verapamil were administered, we observed significant increases in Q-T C intervals [8]. The prolongation of the Q-T C interval was related to the plasma concentrations of both R verapamil and its major metabolite norverapamil.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Verapamil Enantiomers and Metabolites on Cardiac K+ Channels Expressed in Xenopus Oocytes

Waldegger¹,

Niemeyer²,

Mörike

et al. 1999

Cell Physiol Biochem

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The effect of verapamil and its enantiomers and metabolites on cardiac action potential repolarizing potassium channels was tested. For this purpose, the potassium channels Kv1.1, Kv1.5, Kir2.1, and HERG, and the IsK subunit of the IKs-channel complex were expressed in Xenopus oocytes and two-electrode voltage-clamp experiments were performed. Verapamil induced a concentration-dependent block of Kv1.1-, Kv1.5-, IKs-, and HERG-induced currents with IC₅₀ values of 14.0 ± 2.7 μM (n = 4), 5.1 ± 0.5 μM (n = 6), 161.0 ± 26.3 μM (n = 4), and 3.8 ± 0.2 μM (n = 5), respectively. The same potency of HERG channel inhibition was observed for the optical enantiomers (+)-verapamil (IC₅₀ = 3.5 ± 0.4 μM, n = 5) and (–)-verapamil (IC₅₀ = 4.0 ± 0.7 μM, n = 4), as well as the derivatives norverapamil (D591; IC₅₀ = 3.8 ± 0.3 μM, n = 4) and D703 (IC₅₀ = 2.2 ± 0.4 μM, n = 4). The verapamil metabolites D620 and D617 did not block HERG-induced currents at concentrations of up to 30 μM (n = 3). These results demonstrate that cardiac delayed rectifier potassium currents are sensitive targets to calcium channel blockers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%