Age-dependent changes in phenytoin tissue bindings in rats: comparison between in vivo and in vitro tissue-to-blood partition coefficients (Kp values) of phenytoin.

Abstract

Age-dependent changes in phenytoin tissue bindings in rats were investigated by equilibrium dialysis using serum and 10% tissue (brain, lung, liver, kidney and muscle) homogenates. All percentages of phenytoin bound to serum and tissue homogenates were independent of the initial phenytoin concentration (2 to 25 micrograms/ml) in 1-d, 1-, 3- and 8-week-old rats. The percentages bound to serum, brain, liver, kidney and muscle in newborn rats (1-d-old rats) were lower than those in 8-week-old rats and the percentages bound increased gradually in the growth process. However, those in lungs were constant in all ages of rats. It was assumed that the age-dependent changes in phenytoin tissue binding were caused by the changes in the quantities of tissue constituents to which phenytoin bound in the growth process. Tissue-to-blood partition coefficients (Kp values) were calculated from in vitro tissue binding data and the pH-difference across the cell membrane. These Kp values were in good agreement with the in vivo Kp values reported previously. It was concluded that the age-dependent changes in phenytoin tissue distribution were caused by the age-dependent changes in phenytoin binding to blood constituents and tissues but that the change of phenytoin blood binding contributed to the age-dependent changes in Kp values of phenytoin more than to phenytoin tissue binding and consequently the Kp values of phenytoin decreased as rats grew.