Physiologically based pharmacokinetic model for tetrachlorobenzyltoluenes in rat: comparison of in vitro and in vivo metabolic rates.

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.

[1]  M E Andersen,et al.  Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation. , 1997, Toxicology and applied pharmacology.

[2]  M. Feeley,et al.  PCB congener patterns in rats consuming diets containing Great Lakes salmon: analysis of fish, diets, and adipose tissue. , 1999, Environmental research.

[3]  H. Matthews,et al.  Distribution and excretion of 2,2',4,4',5,5'-hexabromobiphenyl in rats and man: pharmacokinetic model predictions. , 1980, Toxicology and applied pharmacology.

[4]  W. Seinen,et al.  Transition metal catalysed cross-coupling between benzylic halides and aryl nucleophiles. Synthesis of some toxicologically interesting tetrachlorobenzyltoluenes , 1998 .

[5]  J. Boer,et al.  Determination of toxaphene in human milk from Nicaragua and in fish and marine mammals from the northeastern Atlantic and the North Sea , 1993 .

[6]  Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  J B Houston,et al.  Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. , 1994, Biochemical pharmacology.

[8]  L. Birnbaum,et al.  Determination of parameters responsible for pharmacokinetic behavior of TCDD in female Sprague-Dawley rats. , 1997, Toxicology and applied pharmacology.

[9]  J B Houston,et al.  Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. , 1997, Drug metabolism reviews.

[10]  R. Lutz,et al.  A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[11]  M E Andersen,et al.  Modeling receptor-mediated processes with dioxin: implications for pharmacokinetics and risk assessment. , 1993, Risk analysis : an official publication of the Society for Risk Analysis.

[12]  Y. Masuda,et al.  Elimination of polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) from human blood in the Yusho and Yu-Cheng rice oil poisonings , 1993, Archives of environmental contamination and toxicology.

[13]  A. Bergman,et al.  Tissue Distribution, Metabolism, and Excretion of 2,4,4'-Trichlorobiphenyl (Cb-28) in the Rat , 1996, Toxicology and industrial health.

[14]  M. van den Berg,et al.  The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity. , 1994, Critical reviews in toxicology.

[15]  M. Bouraly,et al.  Bioaccumulation and elimination of tetrachlorobenzyltoluene (TCBT) by the rat and by fish , 1989 .

[16]  J. DeJongh,et al.  Biotransformation rates of Ugilec 141 (tetrachlorobenzyltoluenes) in rat and trout microsomes. , 2000, Chemosphere.

[17]  J. Houston,et al.  In vivo clearance of ethoxycoumarin and its prediction from In vitro systems. Use Of drug depletion and metabolite formation methods in hepatic microsomes and isolated hepatocytes. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[18]  R. Lutz,et al.  Comparison of the pharmacokinetics of several polychlorinated biphenyls in mouse, rat, dog, and monkey by means of a physiological pharmacokinetic model. , 1984, Drug metabolism and disposition: the biological fate of chemicals.

[19]  R. Obach,et al.  Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[20]  K. Ballschmiter,et al.  Isomer-specific determination of tetrachlorobenzyltoluenes (TCBT) in the technical mixture Ugilec 141 by capillary gas chromatography , 1989 .

[21]  M E Andersen,et al.  A physiologically based pharmacokinetic model for 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) in the rat: tissue distribution and CYP1A induction. , 1993, Toxicology and applied pharmacology.

[22]  H. Matthews,et al.  Pharmacokinetics of PCBs. , 1984, Annual review of pharmacology and toxicology.

[23]  J E Simmons,et al.  Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats. , 1994, Toxicology and applied pharmacology.

[24]  I. Chahoud,et al.  Tissue distribution, toxicokinetics and induction of hepatic drug metabolizing enzymes in male rats after a single s.c. dose of 3,4,3',4'-tetrachlorobiphenyl (PCB-77). , 1997, Chemosphere.

[25]  J Meulenbelt,et al.  Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling. , 2000, Toxicology and applied pharmacology.