Pharmacokinetics pathological changes

Giri, S.N., H.R. Parker, W.L. Spangler, H.P. Misra, G. Ishizaki, M.J. Schiedt, and D.B. Chandler. 1982. Pharmacokinetics of [14C]-paraquat and associated biochemical and pathologic changes in beagle dogs following intravenous administration. Fundam. Appl. Toxicol. 2 261-269. 

Dose selection for subchronic and chronic toxicology studies should be based on the results from acute toxicity studies and pharmacokinetic evaluations. The three typical dose levels are (a) a no-toxic-effect level, which should be at least equivalent to, and hopefully a multiple of, the proposed human dose, (b) a dose level that produces a toxic effect in clinical observations, clinical pathology, or histopathologic changes, and (c) a dose level between these two. 

Fiver disease in humans encompasses a wide range of pathological disturbances that can lead to a reduction in liver blood flow, extrahepatic or intrahepatic shunting of blood, hepatocyte dysfunction, quantitative and qualitative changes in serum proteins, and changes in bile flow. Different forms of hepatic disease may produce different alterations in drug absorption, disposition, and pharmacologic effect. The pharmacokinetic or pharmacodynamic consequences of a specific hepatic disease may differ... 

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