Slow hydroxylation of tricyclic antidepressants--relationship to polymorphic drug oxidation

There are marked interindividual differences in Css of tricyclic antidepressants. These are due mainly to corresponding differences in the rate of oxidative metabolism of these drugs. Twin, family, and cross-over studies with nortriptyline (NT) and desmethylimipramine (DMI) show that their kinetics and hydroxylation (Css, Kel, and Vd) are controlled mainly by genetic factors (in drug-free individuals). Slow hydroxylators are at risk of developing excessive plasma concentrations of NT and DMI when given per se or when formed from the tertiary amines amitriptyline and imipramine. Classic antidepressants have fairly well established concentration-effect curves in endogenous depression. Severe toxicity usually occurs at supratherapeutic plasma levels and might be prevented by tailoring the dosage according to the individual's drug hydroxylating capacity. Monitoring drug plasma levels is particularly relevant in slow hydroxylators (Sjöqvist et al, 1980). There is a strong association between an individual's ability to hydroxylate NT and DMI and his debrisoquine (D) hydroxylation phenotype. The D hydroxylation index will predict the patient's capacity to hydroxylate NT and DMI and hence Css during therapy. Possibly, similar hydroxylases are involved in the 4-hydroxylation of debrisoquine, in the stereospecific E-10-hydroxylation of NT, and in the 2-hydroxylation of DMI. By contrast, demethylation of AT (and probably other tertiary tricyclics) does not significantly correlate to debrisoquine hydroxylation except in non-smoking individuals. The increasing knowledge about the clinical pharmacokinetics of tricyclic antidepressants is a distinct advantage over that of the new generation of antidepressants, where little is known about concentration-effect relationships and factors governing their rate of metabolism. Possible interethnic differences in the metabolism of these essential drugs should be explored in epidemiologically sound investigations.