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>125 50-150

aTotal concentration of the parent compound and the desmethyl metabolite.

Source. Adapted from Nelson JC: "Tricyclic and Tetracyclic Drugs," in Comprehensive Textbook of Psychiatry/VII, 7th Edition. Edited by Kaplan HI, Sadock BJ. Baltimore, MD, Lippincott Williams & Wilkins, 2000, p. 2494. Copyright 2000, Lippincott Williams & Wilkins. Used with permission.

Hepatic metabolism of the tricyclics and tetracyclics occurs along two principal metabolic pathways. Demethylation of the side chain converts the tertiary amines to secondary amines—for example, amitriptyline is converted to nortriptyline—and the characteristics of the compound are altered. The tertiary amines are relatively more serotonergic, whereas the demethylated amines are relatively more noradrenergic. The other pathway in hepatic metabolism is hydroxylation of the ring structure. Hydroxylation results in the formation of hydroxy metabolites. In some cases, the levels of the metabolite are substantial. The concentration of 10-hydroxynortriptyline usually exceeds that of the parent compound (Bertilsson et al. 1979). Usually 2-hydroxydesipramine is present at levels approximately 40%-50% of those present in the parent compound, but these ratios are quite variable, depending on the rate of hydroxylation (Bock et al. 1983; Potter et al. 1979). Thus, in extensive metabolizers, the ratio of hydroxy metabolite to parent compound can be quite high, but total drug levels are low. Hydroxyimipramine and hydroxyamitriptyline are present at very low concentrations and are clinically unimportant. The hydroxy metabolites are then conjugated and excreted. The conjugated metabolites are not active.

Hydroxynortriptyline and hydroxydesipramine both block the norepinephrine transporter (Bertilsson et al. 1979; Potter et al. 1979). Both have been shown to have antidepressant activity (Nelson et al. 1988b; Nordin et al. 1987). The potency of hydroxydesipramine is comparable to that of the parent compound in terms of norepinephrine reuptake blockade. There are two isomers of hydroxynortriptyline, E- and Z-10-hydroxynortriptyline. E-10-hydroxynortriptyline is present at levels four times higher than those of the Z isomer and is about 50% as potent as nortriptyline in blocking norepinephrine uptake. The clinical significance of high levels of less potent hydroxynortriptyline is not entirely clear. In particular, it is not clear whether high levels of less potent hydroxynortriptyline might interfere with the action of nortriptyline—a question of interest because such an effect might explain the therapeutic window described for this drug. Both hydroxynortriptyline and hydroxydesipramine are less anticholinergic than their parent compounds. The hydroxy metabolites may have other effects. Early studies suggested that hydroxynortriptyline concentrations were disproportionately associated with cardiac conduction abnormalities (Schneider et al. 1988; Young et al. 1985), but later studies indicated that the E enantiomer of 10-hydroxynortriptyline was less cardiotoxic (Pollock et al. 1992).

The principal metabolic pathway for amoxapine is hydroxylation, during which 7-hydroxyamoxapine and 8-hydroxyamoxapine are produced (Coupet et al. 1979). These compounds differ:

7-hydroxyamoxapine has high-potency neuroleptic properties but a short half-life;

8-hydroxyamoxapine is metabolized more slowly and appears to contribute to the drug's antidepressant action.

In recent years, identification of the specific isoenzyme pathways involved in the metabolism of a variety of drugs, including the tricyclics, has been the focus of intensive study. The CYP2D6 pathway appears responsible for hydroxylation of desipramine and nortriptyline (Brosen et al. 1991). In fact, desipramine has been considered the prototypic substrate for CYP2D6 because it has no other major metabolic pathways. Demethylation of the tertiary-amine compounds appears to involve a number of CYP isoenzymes, including 1A2, 3A4, and 2C19. These hepatic isoenzymes are under the control of specific genes, and the gene loci have been identified for several of these isoenzymes, including CYP2D6. Approximately 5%-10% of Caucasians are homozygous for the recessive autosomal 2D6 trait, resulting in deficient hydroxylation of desipramine and nortriptyline (Brosen et al. 1985; Evans et al. 1980). These individuals are termed poor metabolizers, while those with adequate 2D6 enzyme are referred to as extensive metabolizers. Approximately 20% of individuals of Asian descent have a genetic polymorphism resulting in deficient CYP2C19 metabolism. This pathway is involved in the metabolism of the tertiary tricyclic compounds.

The variability in plasma concentrations that results from these metabolic differences is substantial. For example, in a sample of 83 inpatients who were given a fixed dose of 2.5 mg/kg of desipramine, we observed steady-state plasma concentrations ranging from 20 ng/mL to 934 ng/mL (Nelson 1984). Even among extensive metabolizers, there can be variability in the rates of metabolism, resulting in the term ultrarapid metabolizers. Various methods have been used to phenotype the individuals who are slow or fast metabolizers. For example, formation of the debrisoquine metabolite in the urine has been used to characterize the metabolic rate of CYP2D6 (Brosen et al. 1991; Evans et al. 1980). Recent work in this area has shifted to genotyping the involved isoenzymes. In clinical practice, blood levels of the compounds themselves are more often used as a crude index of the rate of metabolism.

As noted above, desipramine has often been used as a substrate for 2D6 because 2D6 is the only major metabolic pathway for this compound. While desipramine may be useful for examination of 2D6 inhibition, it may overestimate the magnitude of drug interactive effects for those agents that have multiple pathways.

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