Prediction of diazepam disposition in the rat and

Authors: Yasutaka Igari Yuichi Sugiyama Yasufumi Sawada Tatsuji Iga Manabu Hanano

Publish Date: 1983/12/01

Volume: 11, Issue: 6, Pages: 577-593

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Abstract

A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat incorporating anatomical physiological and biochemical parameters ie tissue volume blood flow rate serum free fraction distribution of diazepam into red blood cells drug metabolism and tissuetoblood distribution ratio The serum free fraction of diazepam was determined by equilibrium dialysis at 37°C and was constant over a wide concentration range Partition of diazepam between plasma and erythrocytes was determined in vitroat 37°C and the resultant bloodtoplasma concentration ratio was constant over a wide concentration range The enzymatic parameters Km Vmaxof the eliminating organs ie liver kidney and lung previously determined using microsomes were used for the prediction The tissuetoblood distribution ratios inferred by inspection of the data when pseudoequilibrium is reached after iv bolus injection of 12 mg/kg diazepam were corrected according to the method of Chen and Gross Predicted diazepam concentration timecourse profiles in plasma and various organs or tissues using an 11compartmental model were compared with those observed Prediction was successful in all compartments including brain the target organ of diazepam Scaleup of the disposition kinetics of diazepam from rat to man was also successfulThis study was supported by a grantinaid for scientific research provided by the Ministry of Education Science and Culture of Japan A portion of the paper appeared in a dissertation submitted by Y Igari to the Graduate Division University of Tokyo in partial fulfillment of the requirement for the PhD degree

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