NONLINEAR KINETICS OF NORTRIPTYLINE IN RELATION TO NORTRIPTYLINE CLEARANCE AS OBSERVED DURING THERAPEUTIC DRUG-MONITORING

From routine therapeutic drug monitoring data, samples from 105 patien ts with two analyses of nortriptyline at different daily doses were co llected. The ratio between concentration and daily dose, which is the reciprocal of the apparent clearance, was compared intraindividually t o study the occurrence of dose-dependent kinetics. Subjects with a low or intermediate ratio at the low dose had a higher mean ratio at the high dose, indicating a nonlinear relationship between dose and concen tration. The magnitude of the difference was inversely correlated to t he ratio at the low dose. No major difference was seen in the ca. 10% of the patients that exhibited the highest ratio at the low dose. This fraction corresponds to the frequency of poor metabolizers of debriso quine in the population. The metabolism of nortriptyline has been show n to be partly dependent on the debrisoquine hydroxylase CYP2D6. We co nclude that dose-dependent kinetics of nortriptyline occurs in subject s with a high or intermediate capacity to eliminate the drug, in accor d with debrisoquine hydroxylase being a high-affinity, low-capacity pa thway in the elimination of nortriptyline.