![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
WJ Crumb and CW Clarkson
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana.
Clinical reports indicate that almost 30% of cocaine overdose-related deaths occur 2 to 5 hr after administration, when an appreciable amount of cocaine can be expected to have been converted to metabolites. We investigated the effects of the three major metabolites of cocaine: benzoylecgonine, ecgonine methyl ester and norcocaine on sodium channels in isolated guinea pig myocytes using the whole cell variant of the patch clamp technique at 16 +/- 0.5 degrees C. Benzoylecgonine and ecgonine methyl ester did not produce a significant block of sodium current at a concentration of 100 microM. In contrast, 30 microM norcocaine was found to reduce sodium current in a use-dependent manner qualitatively similar to cocaine. The time course of sodium current block development and recovery were characterized. With 30 microM norcocaine, two phases of block development were defined: a rapid phase (tau = 11.9 +/- 11.6 msec) and a slow phase (tau = 2.2 +/- 0.5 sec). Recovery from drug-induced block at -140 mV was approximately twice as fast for norcocaine (tau = 4.6 +/- 1.7 sec, n = 7) compared to cocaine (tau = 8.4 +/- 0.9 sec, n = 6). Norcocaine was found to have a higher affinity for inactivated cardiac sodium channels (Kdi = 5.7 +/- 0.9 microM) than cocaine (Kdi = 7.8 +/- 1.2 microM) (P less than .01); however, norcocaine produced less use-dependent block due to its faster unbinding kinetics. These data indicate that although norcocaine and cocaine are potent sodium channel blockers, benzoylecgonine and ecgonine methyl ester are ineffective blockers at clinically relevant concentrations (i.e., less than or equal to 100 microM).
This article has been cited by other articles:
|
|
 |
|
  M. E. O'Leary, M. Digregorio, and M. Chahine Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms Mol. Pharmacol., December 1, 2003; 64(6): 1575 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Bauman and R. J. DiDomenico Cocaine-Induced Channelopathies: Emerging Evidence on the Multiple Mechanisms of Sudden Death Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2002; 7(3): 195 - 202. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Ferreira, W. J. Crumb Jr., C. G. Carlton, and C. W. Clarkson Effects of Cocaine and Its Major Metabolites on the HERG-Encoded Potassium Channel J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 220 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. O'Leary Inhibition of Human Ether-A-Go-Go Potassium Channels by Cocaine Mol. Pharmacol., February 1, 2001; 59(2): 269 - 277. [Abstract] [Full Text]
|
|
|
|
|
|
B. P. Bowman, S. R. Vaughan, Q. D. Walker, S. L. Davis, P. J. Little, N. M. Scheffler, B. F. Thomas, and C. M. Kuhn Effects of Sex and Gonadectomy on Cocaine Metabolism in the Rat J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1316 - 1323. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
