Differences in simulated liver concentrations of toxic coumarin metabolites in rats and different human populations evaluated through physiologically based biokinetic (PBBK) modeling

Coumarin is bioactivated via 3,4-epoxidation resulting in formation of the hepatotoxic o-hydroxyphenylacetaldehyde (oHPA) and detoxified by cytochrome P450 2A6 (CYP2A6) hydroxylation leading to 7-hydroxycoumarin. The present study defines physiologically based biokinetic (PBBK) models to predict liver levels of the toxic oHPA metabolite of coumarin in rats and in human subjects with normal or deficient CYP2A6 catalyzed coumarin 7-hydroxylation. The results reveal that the predicted maximum tissue concentration (C(max)) of oHPA in the liver of wild type human subjects and of subjects deficient in CYP2A6 catalyzed 7-hydroxylation are, respectively, three and one order of magnitude lower than the values predicted for rat liver. Another difference between CYP2A6 deficient and wild type human subjects is a 500-fold difference in the area under the curve 0-24h (AUC(0-24h)) for the time-dependent oHPA liver concentration pointing at a relative higher percentage of the original dose converted in time through this pathway when CYP2A6 is deficient. For wild type human subjects and the subjects with completely deficient coumarin 7-hydroxylation the AUC(0-24h) values for oHPA in the liver are, respectively, three and one order of magnitude lower than that for rat liver. Even when 7-hydroxylation is deficient, the chances on formation of the hepatotoxic oHPA metabolite will be significantly lower in the liver of humans than those expected in the liver of rats when exposed to a similar dose on a body-weight basis. This conclusion should be taken into account when extrapolating data from experimental studies in sensitive animals, i.e., rats, to the general human population.