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http://dx.doi.org/10.4062/biomolther.2007.15.1.040

Antihypertensive Effects of Enantiomers of Amlodipine Camsylate, a Novel Salt of Amlodipine  

Oh, Kwang-Seok (Center for drug discovery technology, Korea Research Institute of chemical Technology)
Kim, Maeng-Sup (Central Research Institute, Hanmi Pharm Co., Ltd.)
Lee, Byung-Ho (Center for drug discovery technology, Korea Research Institute of chemical Technology)
Publication Information
Biomolecules & Therapeutics / v.15, no.1, 2007 , pp. 40-45 More about this Journal
Abstract
The vascular relaxant effects on isolated rat aorta of amlodipine camsylates (S-, R-enantiomer, and R/S-racemate), were evaluated and compared with that of S-amlodipine besylate. Furthermore, antihypertensive effects were measured in spontaneously hypertensive rat (SHR). The S-amlodipine camsylate concentration-dependently inhibited $Ca^{2+}$-induced contraction of rat aorta with a very slow onset of action (reached its maximum at 3.5h; $ED_{50}:\;1.50\;{\pm}\;0.24$ nM), having a potency 2-fold higher than those of R/S-amlodipine camsylate $(ED_{50}:\;3.36\;{\pm}\;0.91\;nM)$ and similar to those of S-amlodipine besylate $(ED_{50}:\;1.44\;{\pm}\;0.14\;nM)$, whereas the R-amlodipine camsylate has 590-fold lower vasorelaxant activity $(ED_{50}:\;886.4\;{\pm}\;49.7\;nM)$. In SHR, orally administered S-amlodipine camsylate produced a dose-dependent and long-lasting (>>10 h) antihypertensive effect $(ED_{20}:\;0.89\;mg/kg)$, with a potency 2-fold higher than those of R/S-amlodipine camsylate $(ED_{20}:\;1.82\;mg/kg)$ and similar to those of S-amlodipine besylate $(ED_{20}:\;0.71\;mg/kg)$. In contrast, the R-amlodipine camsylate has no effect even-though administrated high concentration 10 mg/kg. These results suggest that S-amlodipine camsylate has the potency and long-lasting antihypertensive activity as single enantiomer drug, and its antihypertensive effect is not significantly different to that of S-amlodipine besylate.
Keywords
antihypertension; amlodipine; camsylate; calcium antagonist; spontaneously hypertensive rat;
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1 Burges, R. A., Gardiner, D. G., Gwilt, M., Higgins, A. J., Blackburn, K. J., Campbell, S. F., Cross, P. E. and Stubbs, J. K. (1987). Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors. J. Cardiovasc. Pharmacol. 9, 110-119
2 Arrowsmith, J. E., Campbell, S. F., Cross, P. E., Stubbs, J. K., Burges, R. A., Gardiner, D. G. and Blackburn, K. J. (1986). Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J. Med. Chem. 29, 1696-1702   DOI
3 Beresford, A. P., McGibney, D., Humphrey, M. J., Macrae, P. V. and Stopher, D. A. (1988). Metabolism and kinetics of amlodipine in man. Xenobiotica. 18, 245-254   DOI
4 Burke, D. and Henderson, D. J. (2002). Chirality: a blueprint for the future. Br. J. Anaesth. 88, 563-576   DOI   ScienceOn
5 Abernethy, D. R. (1989). The pharmacokinetic profile of amlodipine. Am. Heart J. 118, 1100-1103   DOI   ScienceOn
6 Dodd, M. G., Gardiner, D. G., Carter, A. J., Sutton, M. R. and Burges, R. A. (1989). The hemodynamic properties of amlodipine in anesthetised and conscious dogs: comparison with nitrendipine and influence of beta-adrenergic blockade. Cardiovasc. Drugs Ther. 3, 545-555   DOI
7 Goldmann, S., Stoltefuss, J. and Born, L. (1992). Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: a correction. J. Med. Chem. 35, 3341-3344   DOI
8 Lee, B. H., Seo, H. W., Kwon, K. J., Yoo, S. E. and Shin, H. S. (1999). In vivo pharmacologic profile of SK-1080, an orally active nonpeptide AT1-receptor antagonist. J. Cardiovasc. Pharmacol. 33, 375-382   DOI   ScienceOn
9 Lee, B. H., Seo, H. W., Yoo, S. E., Kim, S. O., Lim, H. and Shin, H. S. (2001). Differential action of KR-31378, a novel potassium channel activator, on cardioprotective and hemodynamic effects. Drug Dev. Res. 54, 182-190   DOI   ScienceOn
10 Lee, B. H., Yoo, S. E. and Shin, H. S. (1998). Hemodynamic profile of SKP-450, a new potassium-channel activator. J. Cardiovasc. Pharmacol. 31, 85-94   DOI   ScienceOn
11 Lee, J. (2006). S-(-)-Amlodipine camsylate or hydrate thereof and pharmaceutical composition containing salt. KP2006-0068401 (in application)
12 Rentsch, K. M. (2002). The importance of stereoselective determination of drugs in the clinical laboratory. J. Biochem. Biophys. Methods. 54, 1-9   DOI   ScienceOn
13 Meredith, P. A. and Elliott, H. L. (1992). Clinical pharmacokinetics of amlodipine. Clin. Pharmacokinet. 22, 22-31   DOI   ScienceOn
14 Park, J. Y., Kim, K. A., Lee, G. S., Park, P.W., Kim, S. L., Lee, Y. S., Lee, Y. W. and Shin, E. K. (2004). Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects. Clin. Ther. 26, 715-723   DOI   ScienceOn
15 Park, J. Y., Kim, K. A., Park, P. W., Lee, O. J., Ryu, J. H., Lee, G. H., Ha, M. C., Kim, J. S., Kang, S. W. and Lee, K. R. (2006). Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects: a randomized, open-label, two-period, comparative, crossover study. Clin Ther. 28, 1837-1847   DOI   ScienceOn
16 Shin, H. S., Seo, H. W., Yoo, S. E. and Lee, B. H. (1998). Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310. Pharmacology 56, 111-124   DOI   ScienceOn
17 Spargo, P. L. (1995). Separation of the enantiomers of amlodipine via their diastereomeric tartrates. WO9525722
18 Tucker, G. T. (2000). Chiral switches. Lancet. 355, 1085-1087   DOI   ScienceOn
19 Walker, D. K., Humphrey, M. J. and Smith, D. A. (1994). Importance of metabolic stability and hepatic distribution to the pharmacokinetic profile of amlodipine. Xenobiotica. 24, 243-250   DOI
20 Yamanaka, K., Suzuki, M., Munehasu, S. and Ishiko, J. (1991). Antihypertensive effects of amlodipine, a new calcium antagonist. Nippon Yakurigaku Zasshi 97, 115-126   DOI
21 Zhang, X. P., Loke, K. E., Mital, S., Chahwala, S. and Hintze, T. H. (2002). Paradoxical release of nitric oxide by an L-type calcium channel antagonist, the R+ enantiomer of amlodipine. J. Cardiovasc. Pharmacol. 39, 208-214   DOI   ScienceOn