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(R)-Verapamil HCl, the hydrochloride salt of Verapamil R-isomer, is a novel and potent P-Glycoprotein (MRP1, efflux pump in multidrug resistant tumor cells) inhibitor. It blocks MRP1 mediated transport, leading to chemosensitization of MRP1-overexpressing cells to anticancer drugs.
| Targets |
Calcium channel; Ca2+
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|---|---|
| ln Vitro |
(S)-Verapamil hydrochloride (S(-)-Verapamil hydrochloride), but not (R)-Verapamil hydrochloride, effectively kills MRP1-transfected BHK-21 cells[1]. (S)-Verapamil hydrochloride is an excellent active form with low bioavailability[2].
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| ln Vivo |
St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration-time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P <.0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P <.0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P <.01) and 63% (P <.0001), respectively.[2]
Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.[3]
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| Enzyme Assay |
The multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype) has been found to be modulated by racemic verapamil (through stimulation of glutathione transport), inducing apoptosis of human MRP1 cDNA-transfected baby hamster kidney 21 (BHK-21) cells and not of control BHK-21 cells. In this study, we show that the two enantiomers of verapamil have different effects on MRP1 activity. Only the S-isomer (not the R-isomer) potently induced the death of MRP1-transfected BHK-21 cells. The decrease in cellular glutathione content induced by the S-isomer, which was not observed with the R-isomer, was stronger than that induced by the racemic mixture, indicating that the R-isomer antagonized the S-isomer effect. Both enantiomers altered leukotriene C(4) and calcein transport by MRP1. Thus, the R-isomer behaved as an inhibitor, which was confirmed by its ability to revert the multidrug resistance phenotype toward vincristine. Molecular studies on purified MRP1 using fluorescence spectroscopy showed that both enantiomers bound to MRP1 with high affinity, with the binding being prevented by glutathione. Furthermore, conformational changes induced by the two enantiomers (monitored by sodium iodide accessibility of MRP1 tryptophan residues) were quite different, correlating with their distinct effects. (S)-Verapamil induces the death of potentially resistant tumor cells, whereas (R)-verapamil sensitizes MRP1-overexpressing cells to chemotherapeutics. These results might be of great potential interest in the design of new compounds able to modulate MRP1 in chemotherapy[2].
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| Cell Assay |
The L-isomer of verapamil is a more potent calcium antagonist than the D-isomer. We have examined the two stereoisomers of verapamil for their ability to increase the chemosensitivity in vitro of three drug resistant cell lines (2780AD, MCF7/AdrR and H69LX10). Neither racemic verapamil nor its individual isomers had any effect on the drug sensitivity of the parent cell lines (A2780, MCF7 and NCI-H69). Verapamil (6.6 microM) increased the sensitivity of all three resistant cell lines to Adriamycin by 10-12-fold. This activity was concentration dependent and was maximal at 6-7 microM. The increase in sensitivity was only 2-3-fold at 2 microM, the maximum plasma concentration achieved in patients. Both the D- and L-isomers of verapamil alone at 6.6 microM were as effective as racemic verapamil and the D-isomer demonstrated the same concentration dependent activity as racemic verapamil. The total cellular Adriamycin concentration of both 2780AD and MCF7/AdrR was increased by two-fold in the presence of verapamil (6.6 microM). Both D- and L-verapamil alone increased the amount of drug accumulated to the same extent as racemic verapamil. These results indicate that the resistance modification activity of verapamil is not stereospecific. Use of D-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thus D-verapamil may be a more effective resistance modifier in vivo than racemic verapamil[1].
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| Animal Protocol |
Jejunal single-pass perfusion experiments with 120-mg/L (244 micromol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4-formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively[3].
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| References |
[3]. St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clin Pharmacol Ther. 2004 Apr;75(4):298-309.
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| Additional Infomation |
Dexverapamil hydrochloride is a hydrochloride salt resulting from the reaction of equimolar amounts of dexverapamil and hydrogen chloride. It competitively inhibits the multidrug resistance efflux pump P-glycoprotein (MDR-1, EC 3.6.3.44), thereby potentially increasing the effectiveness of a wide range of antineoplastic drugs which are inactivated by MDR-1 mechanisms. Dexverapamil hydrochloride exhibits lower calcium antagonistic activity and toxicity than racemic verapamil hydrochloride. It has a role as an EC 3.6.3.44 (xenobiotic-transporting ATPase) inhibitor. It contains a dexverapamil(1+). It is an enantiomer of a (S)-verapamil hydrochloride.
Dexverapamil Hydrochloride is the R-enantiomer of the calcium channel blocker verapamil. Dexverapamil competitively inhibits the multidrug resistance efflux pump P-glycoprotein (MDR-1), thereby potentially increasing the effectiveness of a wide range of antineoplastic drugs which are inactivated by MDR-1 mechanisms. This agent exhibits decreased calcium antagonistic activity and toxicity compared to racemic verapamil. (NCI04) |
| Molecular Formula |
C27H38N2O4.HCL
|
|---|---|
| Molecular Weight |
491.06256
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| Exact Mass |
476.244
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| Elemental Analysis |
C, 66.04; H, 8.01; Cl, 7.22; N, 5.70; O, 13.03
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| CAS # |
38176-02-2
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| Related CAS # |
(S)-Verapamil hydrochloride;36622-28-3;(S)-Verapamil-d7 hydrochloride;(Rac)-Verapamil-d7 hydrochloride;1188265-55-5;(R)-Verapamil-d7 hydrochloride
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| PubChem CID |
170014
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| Appearance |
White to off-white solid powder
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| Melting Point |
129-131℃
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| LogP |
0.433
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
34
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| Complexity |
606
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)[C@@](CCCN(C)CCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC.Cl
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| InChi Key |
DOQPXTMNIUCOSY-HZPIKELBSA-N
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| InChi Code |
InChI=1S/C27H38N2O4.ClH/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6;/h9-12,17-18,20H,8,13-16H2,1-7H3;1H/t27-;/m1./s1
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| Chemical Name |
(2R)-2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile;hydrochloride
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| Synonyms |
Dexverapamil Hydrochloride; 38176-02-2; (R)-(+)-Verapamil Hydrochloride; (R)-Verapamil Hydrochloride; (R)-Verapamil (hydrochloride); Verapamil hydrochloride, (+)-; (2r)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile hydrochloride(1:1); (+)-verapamil hydrochloride;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~203.64 mM)
H2O : ~100 mg/mL (~203.64 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (10.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (10.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (101.82 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0364 mL | 10.1821 mL | 20.3641 mL | |
| 5 mM | 0.4073 mL | 2.0364 mL | 4.0728 mL | |
| 10 mM | 0.2036 mL | 1.0182 mL | 2.0364 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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