AGE-DEPENDENT CHANGES IN PHENYTOIN TISSUE DISTRIBUTION IN RATS

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Age-dependent changes of phenytoin disposition in rats were studied following intravenous administration of 5,5-[4-^<14>C]-diphenylhydantoin to 1-d, 1-, 3- and 8-week-old rats. The distribution volumes changed similarly to those of warfarin in the growth process of rats. The lower clearances in infant and young rats were considered to be caused by the undeveloped liver function to metabolize phenytoin. The changes of distribution volumes in the growth process of rats were assumed to be based upon not only the changes in blood free fractions but also other factors. In any aged rats, the muscle largely contributed to the distribution of phenytoin in the body and the K_p values in the muscle decreased in the growth process of rats. This change of phenytoin transfer to the muscle affected the decrease of distribution volumes of phenytoin in 8-week-old rats and the distribution volumes of brain, lung and liver in infants and young rats were greater than those in adult rats. The K_p value in the lung in 8-week-old rats was smaller than the values in 1-d, 1-and 3-week-old rats and there was no significant difference in the K_p values in the liver among the 4 ages. These results were different from those in warfarin reported previously and suggested that warfarin and phenytoin bind different macromolecules in the liver and the lung.
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