Pharmacokinetics of MMB4 DMS in rats, rabbits, and dogs following a single IV administration.
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 Cmax (µg/mL) and AUC∞ (µg·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.
Battelle, 505 King Avenue, Columbus, OH 43201, USA. hongs@battelle.org
S Peter
SP
Hong
Seth T
ST
Gibbs
Dean J
DJ
Kobs
Merrill R
MR
Osheroff
Jerry D
JD
Johnson
Brian L
BL
Burback
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004285:Dogs; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D010091:Oximes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D000931:Antidotes; D010091:Oximes; C005514:N,N'-monomethylenebis(pyridiniumaldoxime)
MMB4 DMS; intravenous; pharmacokinetics