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Toxicological Sciences 63, 22-28 (2001)
Copyright © 2001 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Physiologically Based Pharmacokinetic Model for Tetrachlorobenzyltoluenes in Rat: Comparison of in Vitro and in Vivo Metabolic Rates

H. J. Kramer*,1, H. Drenth*, M. vandenBerg*, W. Seinen*,2 and J. DeJongh{dagger}

* Research Institute of Toxicology, Utrecht University, P.O. Box 80176, 3508-TD Utrecht, The Netherlands; and {dagger} Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, Archimedesweg 31, 2333 CM Leiden, The Netherlands

Ugilec 141 is a technical mixture of tetrachlorobenzyltoluenes (TCBTs). It was introduced in the early 1980s as a replacement for polychlorinated biphenyls (PCBs). Based on physicochemical properties and accumulation in the environment, the use of this mixture was prohibited. To gain more insight in the toxicokinetics of these compounds in mammals, rats were exposed to a single iv bolus injection of a mixture of 3 TCBTs. At different time points after dosing, the tissue and blood concentrations of the TCBTs were determined. The adipose tissue is the main storage compartment, followed by skin and muscle. The TCBTs were rapidly eliminated from the liver and the blood, with half lives ranging from 65 to 72 h. Additionally, the tissue concentration data for all 3 TCBTs were analyzed using a physiologically based pharmacokinetic (PB-PK) model. Sensitivity analysis illustrated that the elimination of the TCBTs was not influenced by metabolism only, but also by the blood flow through the liver. Furthermore, the metabolic rates derived from the model were compared to previously reported in vitro metabolic rates. The in vitro values for the TCBTs were only a factor 2 to 3 smaller than the in vivo metabolic rates, indicating the value of in vitro techniques for a priori parameterization of PB-PK models.

Key Words: PB-PK; PCB; rat; in vitro-in vivo extrapolation; partition coefficients; metabolism; toxicokinetics.


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