Nonlinear kinetics of nortriptyline in relation to nortriptyline clearance as observed during therapeutic drug monitoring.

From routine therapeutic drug monitoring data, samples from 105 patients with two analyses of nortriptyline at different daily doses were collected. The ratio between concentration and daily dose, which is the reciprocal of the apparent clearance, was compared intra-individually to 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 concentration. The magnitude of the difference was inversely correlated to the 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 debrisoquine in the population. The metabolism of nortriptyline has been shown to be partly dependent on the debrisoquine hydroxylase CYP2D6. We conclude that dose-dependent kinetics of nortriptyline occurs in subjects with a high or intermediate capacity to eliminate the drug, in accord with debrisoquine hydroxylase being a high-affinity, low-capacity pathway in the elimination of nortriptyline.