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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 16, 2006; DOI: 10.1124/jpet.106.104661

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Received for publication March 23, 2006.
Revised June 14, 2006.
Accepted for publication June 14, 2006.

An Initial Assessment of the Systemic Pharmacokinetics of Botulinum Toxin

Easwaran Ravichandran 1, Yujing Gong 1, Fetweh H Al-Saleem 1, Denise M Ancharski 1, Suresh G Joshi 1, Lance L Simpson 1*

1 Jefferson Medical College

* Address correspondence to: E-mail: lance.simpson{at}jefferson.edu

Abstract

Botulinum toxin is an extraordinarily potent molecule that has an unusually long duration of action. Despite this, there is little information available on natural mechanisms for metabolism or elimination, and virtually no information on pharmacologically-induced mechanisms for metabolism and elimination. Therefore, a number of experiments were performed on laboratory animals that addressed two major issues: a.) the effect of blood on the structure, function and biologic half-life of the toxin, and b.) the effect of neutralizing antibodies on half-life and elimination of circulating toxin. In the first series of studies, the metabolic transformation of toxin was assessed by incubating it in blood for varying lengths of time. At each timepoint, aliquots were examined to determine the amount of toxin, the structure of toxin, the catalytic activity of toxin, and the neuromuscular blocking activity of toxin. This work demonstrated that blood did not alter any characteristic of the toxin molecule. Experiments were also done in which toxin was administered to mice and rats at doses that produced clinical poisoning. The results demonstrated that the elimination half-life for native (non-metabolized) toxin in blood and serum was 230-260 min. During the second series of studies, the rate of elimination of circulating toxin was studied in the presence of antibodies directed against the carboxyterminal half of the toxin molecule. This work demonstrated that neutralizing antibodies: a) enhanced clearance of toxin from the circulation, and b) enhanced tissue accumulation of toxin, particularly in liver and spleen.


Key words: Antitoxin, Botulinum toxin, Elimination, Liver, Metabolism, Spleen


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E. Ravichandran, F. H. Al-Saleem, D. M. Ancharski, M. D. Elias, A. K. Singh, M. Shamim, Y. Gong, and L. L. Simpson
Trivalent Vaccine against Botulinum Toxin Serotypes A, B, and E That Can Be Administered by the Mucosal Route
Infect. Immun., June 1, 2007; 75(6): 3043 - 3054.
[Abstract] [Full Text] [PDF]


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