Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

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概要

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• The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for dichlorodiphenyltrichloroethane [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, DDT] in humans based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing liver compartment, and a central compartment for DDT. Evaluation of the rat model was performed by making comparisons between predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after daily oral treatment with DDT (10 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of DDT in vitro were established from data from rat liver microsomes and from pooled human liver microsomes. The ratio of intrinsic clearance values of DDT based on rat in vivo and rat in vitro experiments was used as the scaling factor for estimating in vivo hepatic intrinsic clearance in humans in the final human PBPK model. These results indicate that a simplified PBPK model for DDT is useful for a forward dosimetry approach in rats and/or humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

著者

• Yamazaki Hiroshi

  Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

• SHIMIZU Makiko

  Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

• MURAYAMA Norie

  Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

• Murayama Norie

  Laboratory Of Drug Metabolism And Pharmacokinetics Showa Pharmaceutical University

• HORIUCHI Kana

  Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

• Takano Ryohji

  Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University

• Kitajima Masato

  Fujitsu Kyusyu Systems

• Shono Fumiaki

  Japan Chemical Industry Associations (JCIA)

• Horiuchi Kana

  Laboratory Of Drug Metabolism And Pharmacokinetics Showa Pharmaceutical University

• Kitajima Masato

  Fujitsu Kyushu System Engineering Co. Ltd.

• Shimizu Makiko

  Laboratory For Genetics Of Allergic Diseases Snp Research Center Riken

• Yamazaki Hiroshi

  Laboratory Of Drug Metabolism And Pharmacokinetics Showa Pharmaceutical University

• Shono Fumiaki

  Japan Chemical Industry Association (JCIA)

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