ToxSci Advance Access published online on December 3, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm277
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Toxicokinetics and Tissue Distribution of Deltamethrin in Adult Sprague-Dawley Rats
* Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602, USA 1 Pharmacology Department, National Institute of Toxicological Research, Korea Food and Drug Administration, 5-Nokbum-dong, Eunpyung-gu, Seoul 122-704, South Korea 2 DuPont Haskell Global Centers for Health and Environmental Sciences, P.O. Box 50, 1090 Elkton Road, Newark, DE 19714 USA
3 Corresponding author: James V. Bruckner, Ph,D., Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30605, Tel. : +1-706-542-5405; Fax: +1-706-542-5358, E-mail address: bruckner{at}rx.uga.edu
Received October 19, 2007; revision received October 19, 2007; accepted October 30, 2007
 |
Abstract |
|---|
The objectives of this study were 2-fold: (1) to characterize the toxicokinetics and dose-dependent systemic/tissue distribution of deltamethrin (DLM) over a range of doses in adult Sprague-Dawley (S-D) rats; (2) to provide comprehensive time-course blood and tissue data for development of a physiologically-based toxicokinetic (PBTK) model for DLM. DLM is one of the more neurotoxic members of a relatively new and commonly-used class of insecticides, the pyrethroids. Despite widespread exposure of the general population to pyrethroids, there is little basic TK data to use in health risk assessments or in development of PBTK models. Male S-D rats were dosed orally with 0.4, 2 or 10 mg DLM/kg dissolved in glycerol formal. Another group received 2 mg/kg iv. Serial blood and tissue samples were taken at sacrifice and analyzed by HPLC for their DLM content, in order to obtain comprehensive time-course data sets for estimation of classical TK, as well as PBTK parameters (e.g., tissues:blood partition coefficients). Gastrointestinal (GI) absorption of DLM was rapid but incomplete. Bioavailability was just 18%. Some 83% of DLM in blood was present in the plasma. Just 0.1 – 0.3% of systemically-absorbed doses reached the brain, the target organ of the bioactive parent compound. Fat, skin and surprisingly, skeletal muscle, accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Tissue distribution was dose-dependent, though generally not proportional to dose. Clearance was dose-independent in this dosage range. The time-profiles were used by Mirfazaelian et al. (2006) to construct and adjust a PBTK model. Much remains to be learned about physiological/biochemical processes and barriers that govern the GI absorption, transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans.
Key Words: pyrethroid; deltamethrin; toxicokinetics; PBTK modeling; bioavailability; tissue distribution.