Pharmacokinetic Parameters Influencing Tissue Specificity in Chemical Carcinogenesis

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Abstract
Highly and specifically (3H)-labeled trans-4-dimethylaminostilbene was orally administered to female Wistar rats in doses ranging from 5 × 10-10 to 2.5 × 10-4 mol/kg. The following parameters were determined: tissue index in several tissues, binding index of liver proteins, rRNA, DNA, plasma proteins and haemoglobin and stomach proteins. Up to a dose of 2.5 × 10-6 mol/kg all parameters remained constant, i.e. binding increased proportionately with the dose. It is concluded that simple and linear kinetics prevail and that a pharmacokinetic threshold does not exist in this dose range. At higher doses deviations from linearity were observed, however, the binding index decreased rather than increased with the dose. The results indicate that reactive metabolites are involved in the acute toxic effects observed in the rat stomach and that proximate or ultimate activation products are distributed in the circulation. Their concentration in the target tissue appears not to be specifically high to account for the tissue susceptibility.

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