Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in immature rats.
The major objective of this project was to characterize the systemic disposition of the pyrethroid, deltamethrin (DLT), in immature rats, with emphasis on the age dependence of target organ (brain) dosimetry. Postnatal day (PND) 10, 21, and 40 male Sprague-Dawley rats received 0.4, 2, or 10 mg DLT/kg by gavage in glycerol formal. Serial plasma, brain, fat, liver, and skeletal muscle samples were collected for up to 510 h and analyzed for DLT and/or 3-phenoxybenzoic acid (PBA) content by high-performance liquid chromatography. Toxicokinetic data from previous experiments of the same design with young adult (PND 90) rats (Kim, K.-B., Anand, S. S., Kim, H. J., White, C. A., and Bruckner, J. V. [2008]. Toxicokinetics and tissue distribution of deltamethrin in adult Sprague-Dawley rats. Toxicol. Sci. 101, 197-205) were used to compare to immature rat data. Plasma and tissue DLT levels were inversely related to age. Preweanlings and weanlings showed markedly elevated brain concentrations and pronounced salivation, tremors, choreoathetosis, and eventual fatalities. Plasma DLT levels did not reliably reflect brain levels over time. Plasma:brain ratios were time and dose dependent, but apparently not age dependent. Brain levels were better correlated with the magnitude of salivation and tremors than plasma levels. Hepatic intrinsic clearance of DLT progressively increased during maturation, as did the hepatic extraction ratio. Thus, limited capacity to metabolically inactivate DLT appeared primarily responsible for the inordinately high target organ doses and acute neurotoxicity in pups and weanling rats. Hepatic blood flow was not rate limiting in any age group. Limited DLT hydrolysis was manifest in vivo in the pups by relatively low plasma PBA levels. Elevated exposure of the immature brain to a pyrethroid may prove to be of consequence for long-term, as well as short-term neurotoxicity.
Kim
Kyu-Bong
KB
Department of Pharmaceutical Engineering, Inje University, Gimhae, Gyongam 621-749, Korea.
Anand
Sathanandam S
SS
Kim
Hyo J
HJ
White
Catherine A
CA
Fisher
Jeffrey W
JW
Tornero-Velez
Rogelio
R
Bruckner
James V
JV
D000367:Age Factors; D000818:Animals; D001264:Athetosis / Q000139:chemically induced / Q000503:physiopathology; D001565:Benzoates / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002819:Chorea / Q000139:chemically induced / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007306:Insecticides / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D008136:Longevity / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D009570:Nitriles / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D011722:Pyrethrins / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012472:Salivation / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014018:Tissue Distribution; D014202:Tremor / Q000139:chemically induced / Q000503:physiopathology
D001565:Benzoates; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; C017618:3-phenoxybenzoic acid