Kinetic studies on drug disposition in rabbits. II. Dose dependent pharmacokinetics of sulfamethizole.
In order to evaluate dose-dependent sulfamethizole (SMZ) kinetics, 100, 300 and 1000 mg of SMZ was constantly infused over 5 min in rabbits and thereafter plasma and urine samples were collected at convenient intervals. When a dose of 100 mg was given, the time course of total plasma concentration followed a biexponential characteristic. For higher doses, plasma decay curves revealed a convex descending feature after the distribution phase. The respective unbound fraction in plasma (fp) at the total plasma concentrations of 200 and 100 micrograms/ml were 0.41 and 0.19. The corresponding total body clearances were 2.6 and 2.2 l/h, indicating that the drug elimination did not contribute to the convex-descending plasma curves. A physiologically based pharmacokinetic model was adapted to various tissue levels of SMZ. No saturable tissue binding was observed and the apparent volume of distribution of SMZ at steady state with a rabbit of 3.3 kg, Vss (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows: Vss = 0.14 + 1.86fp. From this relationship, it was shown that the apparent volume of distribution of SMZ was significantly affected by the unbound fraction in plasma and the dose-dependent kinetics after intravenous administration was due to the decrease of the apparent volume of distribution with time. The tissue distribution study contributed significantly to the understanding of the dose-dependent drug kinetics.
Katayama
K
K
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
Ohtani
H
H
Murai
A
A
Kakemi
M
M
Koizumi
T
T
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D011817:Rabbits / Q000097:blood / Q000378:metabolism*; D013419:Sulfamethizole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013432:Sulfathiazoles / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D001798:Blood Proteins; D013432:Sulfathiazoles; D013419:Sulfamethizole