RT Journal Article
SR Electronic
T1 AN EVALUATION METHOD FOR NONLINEAR LOCAL DISPOSITION IN RAT LIVER AND KIDNEY
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 230
OP 234
DO 10.1124/dmd.32.2.230
VO 32
IS 2
A1 Kato, Takako
A1 Yamaoka, Kiyoshi
A1 Takakura, Yoshinobu
YR 2004
UL http://dmd.aspetjournals.org/content/32/2/230.abstract
AB 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