TY - JOUR T1 - AN EVALUATION METHOD FOR NONLINEAR LOCAL DISPOSITION IN RAT LIVER AND KIDNEY JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 230 LP - 234 DO - 10.1124/dmd.32.2.230 VL - 32 IS - 2 AU - Takako Kato AU - Kiyoshi Yamaoka AU - Yoshinobu Takakura Y1 - 2004/02/01 UR - http://dmd.aspetjournals.org/content/32/2/230.abstract N2 - 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 (CLH), and renal clearance (CLR = CL - CLH), 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 CLR considerably decreased with an increase in plasma concentration, whereas CLH 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. The American Society for Pharmacology and Experimental Therapeutics ER -