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AN EVALUATION METHOD FOR NONLINEAR LOCAL DISPOSITION IN RAT LIVER AND KIDNEY

Department of Biopharmaceutics and Drug Metabolism, School of Graduate Pharmaceutical Science, Kyoto University, Kyoto, Japan

A two-sampling sites method was developed to separately estimate the nonlinear local disposition in the liver and kidney by sampling blood simultaneously from the hepatic vein and an artery after intravenous administration. Using this method, it was attempted to predict the renal elimination from the systemic and hepatic elimination. Etoposide, a substrate of both P-glycoprotein and CYP3A, was used as a model drug. The blood samples from the hepatic vein and an artery were simultaneously taken from a rat after intravenous administration of etoposide at a dose of 20 or 80 mg/kg. At a dose of 20 mg/kg, the total clearance (CL), hepatic clearance (CL_H), and renal clearance (CL_R = CL - CL_H), which were almost constant, were 2.82 ± 0.24, 0.742 ± 0.214, and 2.09 ± 0.34 l/h/kg, respectively. At a dose of 80 mg/kg, CL and CL_R considerably decreased with an increase in plasma concentration, whereas CL_H slightly decreased. By means of the two-sampling sites method, we estimated the local drug disposition in the liver and kidney. The present local pharmacokinetic method would be applicable to assess the local disposition of other drugs that are mainly metabolized in these organs.