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ToxSci Advance Access originally published online on July 11, 2003
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Toxicological Sciences 75, 31-39 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Hydrolysis Kinetics of Propylene Glycol Monomethyl Ether Acetate in Rats in Vivo and in Rat and Human Tissues in Vitro

J. Y. Domoradzki1, K. A. Brzak and C. M. Thornton

Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674

The kinetic equivalency of propylene glycol monomethyl ether (PGME), derived from propylene glycol monomethyl ether acetate (PGMEA), as well as the parent compound (PGME) following intravenous administration to Fischer 344 rats was evaluated. In addition, in vitro hydrolysis rates of PGMEA in blood and liver tissue from rats and humans were determined. The blood kinetics were determined following iv administration to rats of PGME and PGMEA of low [10 and 14.7 mg/kg body weight (bw)] or high (100 and 147 mg/kg) equimolar dosages of PGME and PGMEA, respectively. The blood time courses of PGME elimination for both dosages of both compounds were identical. Half-lives of PGMEA elimination following iv administration of 14.7 or 147 mg PGMEA/kg bw were calculated to be 1.6 and 2.3 min, respectively. Rat and human in vitro hydrolysis rates of PGMEA were determined by incubation of 5 or 50 µg PGMEA/ml in whole blood or liver homogenate. The rate of loss of PGMEA was more rapid in rat blood than in human blood, with hydrolysis half-lives of 36 and 34 min in human blood and 16 and 15 min in rat blood for the 5 and 50 µg/ml concentrations of PGMEA, respectively. In contrast the rate of loss of PGMEA in human and rat liver homogenate incubations was similar, 27–30 min and 34 min, respectively. These data demonstrate the rapid hydrolysis of PGMEA in vivo to its parent glycol ether, PGME and that, once hydrolyzed, the kinetics for PGME derived from PGMEA are identical to that for PGME. This study supports the use of the toxicological database on PGME as a surrogate for PGMEA.

Key Words: propylene glycol monomethyl ether; propylene glycol monomethyl ether acetate; rat metabolism; human metabolism; pharmacokinetics.


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