PHARMACOKINETIC MODEL FOR N-NITROSODIMETHYLAMINE BASED ON MICHAELIS-MENTEN CONSTANTS DETERMINED WITH THE ISOLATED PERFUSED-RAT-LIVER

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4786-4790
Abstract
A pharmacokinetic model was constructed to describe the absorption, distribution and metabolic clearance of N-nitrosodimethylamine. The model is composed of 2 compartments, total body water and the liver, which are linked by blood flow. Metabolic clearance is presumed to occur only in the liver. Liver clearance kinetics was determined with isolated perfused livers. Clearance appeared to obey Michaelis-Menten kinetics with Km = 8.3 .+-. 4.8 .mu.M and Vmax = 0.15 .+-. 0.2 .mu.mol/min .cntdot. liver. The observed value for Km is .apprx. 1 order of magnitude lower than any observed when clearance is determined using liver microsome preparations. The model is used to calculate whole-body clearance of N-nitrosodimethylamine and relative tissue exposure as a function of the route of administration. The calculations are compared with previously published experimental data, and it is shown that the accuracy of the model for low doses is a result of the novel value observed for Km in the perfused liver.