Abstract
It is well known that change in drug distribution occur in association with hepatic disease. The prediction of the variation in the volume of distribution of drugs at steady-state (Vdss) in hepatic disease is very useful for the planning of drug dosage regimens.
In the present study, we tried to develop methodology for estimating Vdss in hepatic disease based on physiological pharmacokinetics. The following two methods were utilized to predict Vdss in hepatic disease (hepatic cirrhosis and hapatitis). Method 1 : Vdss in hepatic disease was predicted assuming that Vdss in hepatic disease is not different from that in the normal condition. Method 2 : it is assumed that hepatic disease could not lead to alterations in the tissue binding but in the plasma binding, Vdss in hepatic disease was calculated according to the mass balance equation (Vdss=7.2+7.8·fP+27·fp/fT ; where fP and fT are plasma and tissue unbound fraction, respectively) by using the data of Vdss and fp in normal condition and that in hepatic disease. In hapatic cirrhosis, a significant correlation between the observed and predicted values according to Method 1 was obtained with a slope of regression line of 0.79 (p<0.001). On the other hand, a significant linear correlation between the observed and predicted values according to Method 2 was obtained with a slope of 1.03 (p<0.001). Furthermore, a significant difference in percent errors between the two methods was observed (p<0.05). In hepatitis, same resuls were also obtained.
In conclusion, it is suggested that the extent of intrinsic tissue binding of various drugs is little altered in hepatic disease. The prediction of the apparent volume of distribution in hepatic disease according to Method 2 was successful for most drugs studied and very useful for clinical use.
