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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 6, 2008; DOI: 10.1124/jpet.108.136242

0022-3565/08/3263-856-863$20.00
JPET 326:856-863, 2008
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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

The Role of Systemic Handling in the Pathophysiologic Actions of Botulinum Toxin

Fetweh H. Al-Saleem, Denise M. Ancharski, Easwaran Ravichandran, Suresh G. Joshi, Ajay K. Singh, Yujing Gong, and Lance L. Simpson

Departments of Medicine (F.H.A.-S., D.M.A., E.R., S.G.J., A.K.S., Y.G., L.L.S.) and Biochemistry and Molecular Biology (L.L.S.), Jefferson Medical College, Philadelphia, Pennsylvania

The ability of botulinum toxin to poison cholinergic nerve transmission is a dynamic phenomenon that involves not only the actions of the toxin on the body but also the actions of the body on the toxin. The former has been the subject of intense research, whereas the latter has received almost no attention. Therefore, a series of studies were performed to characterize systemic handling of botulinum toxin. The results indicated that the toxin reaches the general circulation (transcytosis across epithelial cells) without obvious changes in structure or biological activity. The general circulation acts as a holding compartment until there is adequate fractional distribution to neuromuscular junctions to produce blockade of transmission. During its transit through this compartment, the toxin 1) undergoes little biotransformation, 2) does not accumulate significantly in circulating cells, and 3) remains largely in the free state. In naive animals, the t1/2 for toxin in the general circulation is approximately 10 h, and at any given point in time, there is little uptake in nontarget organs (liver, kidney, heart, and lung). In immunized animals, toxin clearance from the general circulation is rapid, and there is substantial accumulation of antibody-antigen complexes in liver. Thus, enhanced clearance from the circulation is a major mechanism by which active immunization can protect against poisoning.

Received January 7, 2008; accepted June 5, 2008.

Address correspondence to: Dr. Lance L. Simpson, Department of Medicine, Jefferson Medical College, 1020 Locust Street, Room 314, Philadelphia, PA 19107. E-mail: lance.simpson{at}jefferson.edu






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