Clinical pharmacology of antidepressant drugs: pharmacogenetics

There are marked interindividual differences in Css of tricyclic antidepressants. These are due mainly to corresponding differences in the rate of elimination of the drugs and hence in drug oxidation. Twin, family, and cross-over studies with NT and DMI show that their kinetics (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 AT 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. There is a strong association between an individual's ability to hydroxylate NT and DMI and his D hydroxylation phenotype. The ratios between D and 4-OH-D in urine after a single oral dose are bimodally distributed in the population (polymorphism), with 3 to 10% being slow hydroxylators and the remainder rapid hydroxylators. Indices of NT-hydroxylation do not sharply distinguish the two phenotypes. The D metabolic 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. The increasing knowledge of 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.