4.0 Article

Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a Single IV Administration

期刊

INTERNATIONAL JOURNAL OF TOXICOLOGY
卷 32, 期 -, 页码 30S-37S

出版社

SAGE PUBLICATIONS INC
DOI: 10.1177/1091581813488954

关键词

MMB4 DMS; intravenous; pharmacokinetics

资金

  1. United States Army
  2. Chemical Biological Medical Systems (CBMS)/Medical Identification and Treatment Systems (MITS) [SP0700-00-D-D3180]

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Organophosphorus (OP) nerve agents pose tremendous threats to both military and civilian populations. The substance 1,1'-methylenebis[4-[(hydroxyimino) methyl]-pyridinium] (MMB4) is being developed as a replacement for the currently fielded 2-pyridine aldoxime, or pralidoxime (2-PAM) as a treatment for OP nerve agent-induced toxicity. The present study characterized pharmacokinetic (PK) profiles of MMB4 in male and female Sprague-Dawley rats, New Zealand White rabbits, and beagle dogs given a single intravenous (IV) administration of MMB4 dimethanesulfonate (DMS) at 55, 25, and 15 mg/kg dose, respectively. The plasma MMB4 concentration versus time profiles were biphasic for all species tested and fit a 2-compartment model with first-order elimination. There were no overt sex-related differences in the calculated PK parameters. For the rat, rabbit, and dog, the average systemic exposure parameters predicted C-max (mu g/mL) and AUC(infinity) (mu g.h/mL) were 273 and 71.0, 115 and 48.1, and 87.4 and 39.6; the average volume of distribution (mL/kg) values to the central and peripheral compartments were 207 and 143, 242 and 172, and 198 and 213; and the average elimination half-life (hour) and clearance (mL/h/kg) values were 0.18 and 778, 0.29 and 577, and 0.32 and 430, respectively, when the PK parameters for males and females were combined. The current study revealed a similarity in the volume of distribution to the central compartment for MMB4 among the 3 species tested while demonstrating species-related differences in the elimination half-life and clearance of MMB4.

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