Comparison of the Effects of Methadone and Heroin on Human ether-à-go-go-Related Gene Channels
Tóm tắt
Torsades de pointes (TdP) is a life-threatening form of ventricular arrhythmia that occurs under conditions of delayed cardiac repolarization indicated by prolonged QT intervals in ECG recordings. The main mechanism of QT prolongation and TdP is block of the rapid component of the cardiac delayed rectifier K+ current (IKr), which is encoded by hERG (human ether-à-go-go-related gene). The opioid agonist methadone has previously been demonstrated to inhibit hERG currents, and there are reports of serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation in patients taking methadone. The aim of the present study was to compare the effects of the opioid agonists methadone and heroin (3,6-diacetylmorphine) on hERG currents stably expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both methadone and heroin inhibit hERG currents in a concentration-dependent manner. The following values were calculated for IC50 (concentration causing half-maximal inhibition) and n (the Hill coefficient): 4.8 μM and 0.9 for methadone, 427 μM and 0.7 for heroin. In conclusion, the potency for block of hERG currents is about 100-fold lower for heroin when compared to methadone.
Tài liệu tham khảo
Keating, M. T., & Sanguinetti, M. C. (1996). Molecular genetic insights into cardiovascular disease. Science, 272, 681–685.
Warmke, J. W., & Ganetzky, B. (1994). A family of potassium channel genes related to eag in Drosophila and mammals. Proceedings of the National Academy of Sciences of the United States of America, 91, 3438–3442.
Sanguinetti, M. C., Jiang, C., Curran, M. E., & Keating, M. T. (1995). A mechanistic link between an inherited and an acquired cardiac arrhythmia. Cell, 81, 299–307.
Trudeau, M. C., Warmke, J. W., Ganetzky, B., & Robertson, G. A. (1995). hERG, a human inward rectifier in the voltage-gated potassium channel family. Science, 269, 92–95.
Recanatini, M., Poluzzi, E., Masetti, M., Cavalli, A., & De Ponti, F. (2005). QT prolongation through hERG K+ channel blockade: Current knowledge and strategies for the early prediction during drug development. Medicinal Research Reviews, 25, 133–166.
Redfern, W. S., Carlsson, L., Davis, A. S., Lynch, W. G., MacKenzie, I., Palethorpe, S., et al. (2003). Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovascular Research, 58, 32–45.
International conference on harmonization S7B guideline (CPMP/ICH/423/02; 2005). The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. http://www.emea.europa.eu/pdfs/human/ich/042302en.pdf.
Katchman, A. N., McGroary, K. A., Kilborn, M. J., Kornick, C. A., Manfredi, P. L., Woosley, R. L., et al. (2002). Influence of opioid agonists on cardiac human ether-a-go-go-related gene K+ currents. Journal of Pharmacology and Experimental Therapeutics, 303, 688–694.
Eap, C. B., Crettol, S., Rougier, J.-S., Schläpfer, J., Sintra Grilo, L., Deglon, J.-J., et al. (2007). Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clinical Pharmacology and Therapeutics, 81, 719–728.
Krantz, M. J., Martin, J., Stimmel, B., Mehta, D., & Haigney, M. C. P. (2009). QTc interval screening in methadone treatment. Annals of Internal Medicine, 150, 387–395.
Lin, C., Somberg, T., Molnar, J., & Somberg, J. (2009). The effects of chiral isolates of methadone on the cardiac potassium channel IKr. Cardiology, 113, 59–65.
Hamill, O. P., Marty, A., Neher, E., Sakmann, B., & Sigworth, F. J. (1981). Improved patch-clamp techniques for high-resolution current recordings from cells and cell-free membrane patches. Pfluegers Archiv, 391, 85–100.
de Vos, J. W., Geerlings, P. J., van den Brink, W., Ufkes, J. G., & van Wilgenburg, H. (1995). Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. European Journal of Clinical Pharmacology, 48, 361–366.
Romach, M. K., Piafsky, K. M., Abel, J. G., Khouw, V., & Sellers, E. M. (1981). Methadone binding to orosomucoid (alpha 1-acid glycoprotein): Determinant of free fraction in plasma. Clinical Pharmacology and Therapeutics, 29, 211–217.
Inturrisi, C. E., Colburn, W. A., Kaiko, R. F., Houde, R. W., & Foley, K. M. (1987). Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clinical Pharmacology and Therapeutics, 41, 392–401.
Benmebarek, M., Devaud, C., Gex-Fabry, M., Powell Golay, K., Brogli, C., Baumann, P., et al. (2004). Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clinical Pharmacology and Therapeutics, 76, 55–63.
Rook, E. J., Huitema, A. D. R., van den Brink, W., van Ree, J. M., & Beijnen, J. H. (2006). Population pharmacokinetics of heroin and its major metabolites. Clinical Pharmacokinetics, 45, 401–417.
Cohn, G. L., Cramer, J. A., McBride, W., Brown, R. C., & Kleber, H. D. (1974). Heroin and morphine binding with human serum proteins and red blood cells. Proceedings of the Society for Experimental Biology and Medicine, 147, 664–666.
Mitcheson, J. S., Chen, J., Lin, M., Culberson, C., & Sanguinetti, M. C. (2000). A structural basis for drug-induced long QT syndrome. Proceedings of the National Academy of Sciences of the United States of America, 97, 12329–12333.
Sanguinetti, M. C., & Mitcheson, J. S. (2005). Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends in Pharmacological Sciences, 26, 119–124.
Zünkler, B. J. (2006). Human ether-a-go-go-related (hERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Pharmacology and Therapeutics, 112, 12–37.
Milnes, J. T., Crociani, O., Arcangeli, A., Hancox, J. C., & Witchel, H. J. (2003). Blockade of hERG potassium currents by fluvoxamine: Incomplete attenuation by S6 mutations at F656 or Y652. British Journal of Pharmacology, 139, 887–898.
Mitcheson, J. S. (2003). Drug binding to hERG channels: Evidence for a “non-aromatic” binding site for fluvoxamine. British Journal of Pharmacology, 139, 883–884.
Stork, D., Timin, E. N., Berjukow, S., Huber, C., Hohaus, A., Auer, M., et al. (2007). State dependent dissociation of hERG channel inhibitors. British Journal of Pharmacology, 151, 1368–1376.