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.
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.
Department of Hospital Pharmacy, Toyama Medical and Pharmaceutical University, Japan.
Y
Y
Kato
J
J
Hirate
K
K
Sakaguchi
M
M
Ueno
I
I
Horikoshi
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001834:Body Water / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010672:Phenytoin / Q000097:blood / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D010672:Phenytoin