Pharmacokinetic Interactions

Recently, pharmacokinetic interactions have received considerable attention. One type of pharmacokinetic interaction is enzyme inhibition. A number of drugs can block the metabolic pathways of the tricyclics, resulting in higher and potentially toxic levels. Desipramine has been of particular interest because its metabolism is fairly simple, occurring via the CYP2D6 isoenzyme. Because there are no major alternative pathways, inhibition of CYP2D6 can result in very high desipramine plasma levels, and toxicity can occur (Preskorn et al. 1990). A number of drugs inhibit 2D6. Quinidine, mentioned above, is a very potent 2D6 inhibitor. Other drugs commonly used in psychiatry that inhibit CYP2D6 include the SSRIs fluoxetine and paroxetine, duloxetine, bupropion, and some antipsychotics. Fluoxetine and paroxetine at usual doses raise desipramine levels, on average, three- to fourfold in extensive metabolizers (Preskorn et al. 1994). In slow metabolizers, enzyme inhibitors have less of an effect, because the patients are already deficient in the enzyme and the drug level is already high. In ultrarapid metabolizers, fluoxetine and paroxetine may cause a greater increase in desipramine levels, but these patients are likely to have very low initial desipramine levels. Sertraline 50 mg/day increases desipramine levels, on average, about 30%-40%, which is not a clinically meaningful difference (Preskorn et al. 1994). At higher doses, there is proportionally greater inhibition, but the increase is still substantially less than the 300%-400% increase that occurs with fluoxetine or paroxetine. The magnitude of the effect of bupropion on CYP2D6 has not been reported but appears to be clinically significant. Venlafaxine, nefazodone, mirtazapine, and citalopram appear to have minimal effects on 2D6. 2D6 inhibitors would be expected to block nortriptyline metabolism, but the magnitude of this interaction has not been well studied.

Antipsychotic agents such as chlorpromazine and perphenazine also inhibit 2D6 (Gram et al. 1974; Nelson and Jatlow 1980). At usual doses, perphenazine raises desipramine levels, on average, twofold, but this effect varies with dose and with the neuroleptic employed. Haloperidol can also inhibit the CYP2D6 pathway, but in this author's experience, this effect is not likely to be clinically meaningful at low dosages (e.g., <10 mg/day).

Because the tertiary tricyclics are metabolized by several pathways (CYP1A2, 3A4, 2C19), a selective inhibitor of one pathway would be likely to have less of an effect on these compounds. Drug interactions with the tertiary amines do occur but appear to be less robust. Methylphenidate appears to inhibit demethylation of imipramine to desipramine. At this point, numerous drug interactions have been described, although many are of doubtful clinical significance (for comprehensive reviews, see Nemeroff et al. 1996; Pollock 1997).

The other type of pharmacokinetic drug interaction is enzyme induction. The result of this interaction may render the drug acted upon ineffective. Unlike enzyme inhibition, which occurs quickly, enzyme induction requires synthesis of new enzyme. As a result, the full effect of an enzyme inducer may take 2-3 weeks to develop. If the inducer is discontinued, the effect takes 2-3 weeks to dissipate. Barbiturates and carbamazepine are potent inducers of CYP3A4. Phenytoin also can induce this enzyme, but its effects on the tricyclics appear to be less dramatic. Although CYP2D6 is a noninducible isoenzyme, phenobarbital reduces the availability of desipramine substantially. Apparently when CYP3A4 is induced, it becomes an important metabolic pathway for desipramine and the other tricyclics. In this author's experience, it can be difficult to attain an effective blood level of desipramine in the presence of a barbiturate.

Nicotine induces the CYP1A2 pathway and may lower concentrations of the tertiary tricyclics, but the secondary tricyclics (e.g., desipramine, nortriptyline) appear to be less affected.

Alcohol has a complicated interaction with the tricyclics. Acute ingestion of alcohol can reduce first-pass metabolism, resulting in higher tricyclic levels. Because tricyclic overdose is often associated with alcohol ingestion, this is an important interaction, resulting in higher tricyclic levels. Alternatively, chronic use of alcohol appears to induce hepatic isoenzymes and may lower tricyclic levels (Shoaf and Linnoila 1991).

The tricyclics themselves produce some enzyme inhibition, but few clinically significant interactions have been described. The tertiary tricyclics compete with warfarin for some metabolic enzymes (e.g., CYP1A2) and may raise warfarin levels.

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