Kinetic Studies on Drug Disposition in Rabbits. II. Dose Dependent Pharmacokinetics of Sulfamethizole

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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 (f_p) at the total plasma concentrations of 200 and 100 μg/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, V_<ss> (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows : V_<ss>=0.14+1.86f_p. 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.
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Kinetic Studies on Drug Disposition in Rabbits. II. Dose Dependent Pharmacokinetics of Sulfamethizole

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