Kinetic analysis of phenytoin disposition in rats with experimental renal and hepatic diseases.
The pharmacokinetics of phenytoin (DPH) was investigated in rats with uranyl nitrate induced renal failure, and with D-galactosamine induced hepatic failure. The serum disappearance of DPH after 10 mg/kg i.v. dose followed a two-exponential decline in normal and both types of intoxicated rats. The serum disappearance half-life (t1/2) and the volume of distribution (Vd) significantly increased in both types of intoxicated rats, while the total blood clearances (CLb) significantly decreased. The serum unbound fraction (fu) of DPH significantly increased in both types of intoxicated rats. The blood to plasma concentration ratio (RB) of DPH significantly increased in the uranyl nitrate-treated rats, while that of the D-galactosamine-treated rats did not show significant alteration. The tissue to serum concentration ratios (Kp) of most of tissues studied after i.v. bolus injection of DPH increased in both types of intoxicated rats. Except for the lung of the D-galactosamine-treated rats, the tissue to serum unbound concentration ratio (Kpu) of other tissues did not show a significant alteration. This suggested that the tissue uptake and/or binding of DPH is not affected by uranyl nitrate or D-galactosamine intoxication and that the increases in Vd and Kp are due mainly to the decrease in serum protein binding. The hepatic intrinsic clearance of unbound DPH (CLuint,H) also decreased in both types of intoxicated rats. Thus, the uranyl nitrate and D-galactosamine intoxication caused the increase in fu and the decrease in CLuint,H and these results may explain the significant decrease in CLb and increases in Vd and t1/2. The tissue concentration-time courses of DPH were predicted by a physiciologically based pharmacokinetic model and good agreement between the predicted and observed values in normal and in both types of intoxicated rats were obtained for serum, liver, kidney, brain and muscle.
Itoh
T
T
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Sawada
Y
Y
Lin
T H
TH
Iga
T
T
Hanano
M
M
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005688:Galactosamine / Q000633:toxicity; D008297:Male; D008954:Models, Biological; D010672:Phenytoin / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014502:Uranyl Nitrate / Q000633:toxicity
D014502:Uranyl Nitrate; D010672:Phenytoin; D005688:Galactosamine