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J.Health Sci., 56(5), 557-565, 2010
-Regular Article-
Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling
Ryohji Takano,a, b Norie Murayama,a
Kana Horiuchi,a Masato Kitajima,b
Fumiaki Shono,c and Hiroshi Yamazaki*, a, d
aLaboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543,
bFujitsu Kyusyu Systems, Momochihama, Sawara-ku, Fukuoka 814-8589,
cJapan Chemical Industry Association (JCIA), 1-4-1 Shinkawa, Chuo-ku, Tokyo 104-0033, Japan and
dHigh Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa, Gakuen, Machida, Tokyo 194-8543, Japan
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for 1,4-dioxane in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a developed PBPK model in rats. The model consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for 1,4-dioxane. Evaluation of the rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after daily oral treatment with 1,4-dioxane (500 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of 1,4-dioxane in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. 1,4-Dioxane was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for 1,4-dioxane is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.
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