Kinetics of meperidine N-demethylation in the perfused rat liver preparation

Meperidine and normeperidine elimination was studied in the once-through perfused rat liver preparation. Biliary excretion of these bases was minimal, and nonlinear metabolism of meperidine (extraction ratio of 1.0 to 0.89 at 1 to 19 micrograms/ml) and normeperidine (extraction ratio of 0.6 to 0.1 at 1 to 25 micrograms/ml) was observed when input concentration was increased. The rate of efflux of normeperidine in hepatic venous blood represented an increasing proportion of the rate of presentation and the rate of loss of meperidine (34 to 92%) at increasing meperidine input concentration. But when the data were corrected for the nonlinear sequential metabolism of normeperidine, the rate of N-demethylation accounted completely for the rate of metabolism of meperidine. These N-demethylation rates obeyed Michaelis-Menten behavior, and appeared to be saturated at input meperidine concentration greater than 5 micrograms/ml.