359471.fig.002a
(a)
359471.fig.002b
(b)
Figure 2: Exploration of which toxicokinetic metric is toxicodynamically relevant. Severity grade of liver toxicity (points) in relation to (a) the peak concentration in the liver ( 𝜇 g/g liver tissue) for coumarin in rat. (b) AUC in the liver ( 𝜇 g/g × h) for coumarin in rat. A toxicokinetic model has been constructed for the rat, and 𝐶 m a x and AUC were simulated with doses and duration of exposure taken from published studies ( 𝑛 = 1 1 ). The toxicological endpoint in the studies was liver toxicity the degree of which differed, and we graded the toxicity in a scale from 0 to 4. 𝐶 m a x in the liver (liver peak concentration) was better correlated to liver toxicity than AUC in the liver indicating that it 𝐶 m a x in the liver is the toxicologically relevant toxicokinetic metric.