Pharmacokinetic Model for N-Nitrosodimethylamine Based on Michaelis-Menten Constants Determined with the Isolated Perfused Rat Liver¹

A pharmacokinetic model was constructed to describe the absorption, distribution, and metabolic clearance of N-nitrosodimethylamine. The model is composed of two 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 K_m = 8.3 ± 4.8 µm and V_max = 0.15 ± 0.02 µmol/min·liver. The observed value for K_m is about 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 K_m in the perfused liver.