THE USE OF THERAPEUTIC DRUG-MONITORING DATA TO DOCUMENT KINETIC DRUG-INTERACTIONS - AN EXAMPLE WITH AMITRIPTYLINE AND NORTRIPTYLINE

Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyl ine (NT) collected during 10 years (total of 4,278 analyses in 2,937 p atients) were evaluated to study how other drugs affect the kinetics a t steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared w ith that in patients on different concomitant drugs. Patients on pheno thiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highes t values were seen with levomepromazine and thioridazine. On the contr ary, the mean C/D of both AT and NT in patients on carbamazepine was a bout 50% lower than in those treated with the antidepressant only. Ben zodiazepines did not affect the steady-state kinetics of AT or NT. Int raindividual comparisons of the ratio C/D in subjects with analyses pe rformed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D 6) inhibit the metabolism of NT and that carbamazepine induces the met abolism of both AT and NT. Modeling of the dose dependency of the NT i nteractions with levomepromazine, perphenazine, and thioridazine revea led that the ratio C/D was most affected at low doses of the antidepre ssant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients wit h interacting drugs, which means that many patients treated with pheno thiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The pr esent study shows that therapeutic drug monitoring may serve as a valu able tool to discover and quantify drug interactions.