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Age-dependent changes in phenytoin tissue distribution in rats
Y Kato1, J Hirate, K Sakaguchi
1Department of Hospital Pharmacy, Toyama Medical and Pharmaceutical University, Japan.
Insights
Phenytoin disposition changes with age in rats due to developing liver function and altered tissue distribution. Muscle uptake decreases with age, impacting overall distribution volumes in growing rats.
Area of Science:
- Pharmacokinetics
- Developmental Biology
- Drug Metabolism
Background:
- Phenytoin is an anticonvulsant drug with a narrow therapeutic index.
- Understanding age-dependent drug disposition is crucial for optimizing dosing regimens.
- Previous studies have investigated warfarin disposition in developing rats, providing a comparative basis.
Purpose of the Study:
- To investigate the age-dependent changes in phenytoin disposition in rats.
- To elucidate the factors influencing phenytoin distribution and clearance in different age groups.
- To compare phenytoin's tissue distribution characteristics with those of warfarin.
Main Methods:
- Intravenous administration of radiolabeled phenytoin (5,5-[4-14C]-diphenylhydantoin) to rats of varying ages (1-day, 1-, 3-, and 8-week-old).
- Measurement and analysis of phenytoin distribution volumes, clearances, and tissue-to-plasma concentration ratios (Kp values).
- Comparison of pharmacokinetic parameters across different developmental stages.
Main Results:
- Distribution volumes showed age-dependent changes, similar to warfarin.
- Lower phenytoin clearances in younger rats were attributed to immature liver metabolism.
- Muscle was a major distribution site, with decreasing Kp values in older rats, affecting overall distribution volumes.
Conclusions:
- Phenytoin disposition is significantly influenced by age-related changes in liver function and tissue distribution in rats.
- Differences in tissue binding macromolecules between phenytoin and warfarin were suggested based on distinct distribution patterns in the liver and lung.
- These findings highlight the importance of developmental stage in understanding phenytoin pharmacokinetics.
Abstract:
Age-dependent changes of phenytoin disposition in rats were studied following intravenous administration of 5,5-[4-14C]-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 Kp 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 Kp 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 Kp 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.