Evidence-Based Reviews

Beware cytochrome P450 inducers: Prescribing tips to prevent drug-drug interactions

Current Psychiatry. 2002 November;1(11):11-16

Hepatic enzyme induction—triggered by medications, smoking, or alcohol— can erode the effectiveness of most psychotropics. Here’s how to beat the system.

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References

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9. Nelson JC. Combined treatment strategies in psychiatry. J Clin Psychiatry 1993;54 (suppl 9):42-9.

10. Leinonen E, Lillsunde P, Laukkanen V, et al. Effects of carbamazepine on serum antidepressant concentration in psychiatric patients. J Clin Psychopharmacology 1991;11:313-18.

11. Ketter TA, Jenkins JB, Schroeder DH, et al. Carbamazepine but not valproate induces buproprion metabolism. J Clin Psychopharmacology 1995;15:327-33.

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Psychiatrists know that common psychotropic medications can inhibit the liver’s cytochrome P450 enzyme system, increasing both plasma levels and the toxicity of co-administered drugs. Less well-known, perhaps, is that the opposite process—hepatic enzyme induction—can accelerate the liver’s meolism of co-administered drugs, resulting in abnormally low plasma levels.

Hepatic enzyme-inducing agents may appear in a patient’s regimen by prescription or self-administration (e.g., cigarette smoking, use of St. John’s wort, etc.) (Table 1). Most psychotropics are metabolized by the liver, and co-administering them with a hepatic enzyme inducer may cause pharmacokinetic consequences, including lowered plasma levels of the parent compound and elevated plasma levels of its metabolites. These plasma level changes may result in:

reduced efficacy (e.g., if the parent drug alone is responsible for clinical benefit)
greater efficacy (e.g., with the prodrug codeine, where the analgesic effect may be amplified by accelerated metabolism into its active drug, morphine)
or no change in clinical effect (e.g., if the metabolite of the parent drug is active and its increased plasma level sufficiently compensates for the decreased plasma level of the parent compound).

This article offers an overview of common inducers and the drugs they affect, as well as five principles that can help you anticipate and manage potential drug-drug interactions.

Table 1

COMMON AGENTS ASSOCIATED WITH HEPATIC ENZYME INDUCTION

Prescription	Nonprescription
Carbamazepine	Chronic cigarette smoking
Dexamethasone	Chronic ethanol use
Isoniazid	Chronic marijuana smoking
Modafinil	St. John’s wort
Omeprazole
Oxcarbazepine
Phenobarbital
Phenytoin
Prednisone
Primidone
Rifampin

Carbamazepine

Carbamazepine is the best-known and most-thoroughly documented agent that can induce hepatic enzymes and lower plasma levels of co-administered drugs, both psychiatric and nonpsychiatric. This anticonvulsant also shows evidence of autoinduction, the unusual property of inducing its own accelerated hepatic metabolism.¹

Carbamazepine is a powerful inducer of CYP3A, the most abundant family of cytochrome P450 enzymes.² With initial carbamazepine therapy, hepatic enzyme induction begins within 3 to 5 days and is complete within 21 to 28 days.³ Because any co-administered drug requires some (often unknown) minimum plasma concentration for efficacy—and sometimes requires a “therapeutic window” level⁴— an inducing agent such as carbamazepine may compromise the other drug’s effectiveness.

Effect on neuroleptics. Drugs and classes of psychotropics whose levels and/or efficacies may be reduced in the presence of enzyme-inducing agents are listed in Table 2. For example, when carbamazepine and haloperidol are co-administered, haloperidol plasma levels may be reduced by 60%.⁵ The literature also shows a 50% reduction in fluphenazine levels⁶ and substantially reduced levels of valproic acid,⁷ clozapine,⁸ and perphenazine⁹ when co-administered with carbamazepine. Data on how these changes alter the drugs’ clinical effects are mixed: some patients have improved, and some have worsened.

It is unclear whether carbamazepine’s presence may lower drug levels into or below a neuroleptic plasma “therapeutic window,” or whether some observed patient improvement might occur as an independent augmenting effect of carbamazepine. Clearly, however, the presence or addition of the inducing agent—carbamazepine—substantially lowers neuroleptic plasma levels.

Effect on antidepressants. Carbamazepine has similar plasma level-reducing effects on antidepressants:

amitriptyline and nortriptyline levels have been shown to be reduced by 40%¹⁰
bupropion peak levels are decreased by 87%¹¹
levels of clomipramine,¹² imipramine,¹³ and doxepin show marked reductions.¹⁰

No data have been reported regarding levels of selective serotonin reuptake inhibitors (SSRIs) when co-administered with carbamazepine. Perhaps this is because serotonergic antidepressant plasma levels are not generally measured in clinical practice, as SSRIs are not associated with the risks and toxicities that may occur with high plasma levels of tricyclic antidepressants.⁴ The clinician, however, may extrapolate from carbamazepine’s plasma-lowering effect on other agents and apply the same caution when co-administering serotonergic antidepressants.

Table 2

PSYCHOTROPICS AFFECTED* BY HEPATIC ENZYME INDUCERS

Antidepressants (tricyclics and potentially SSRIs)
Antipsychotics (neuroleptics and atypicals)
Benzodiazepines
Bupropion
Valproate
* Exhibit reduced plasma levels and/or impaired efficacy when co-administered

Effect on other medications. Carbamazepine’s hepatic enzyme induction also may lower alprazolam levels by more than 50%,¹⁴ risking sedative-hypnotic withdrawal in the dependent patient. Valproate levels have been reduced by more than 60% when co-administered with carbamazepine. Carbamazepine can also reduce the levels and efficacy of common nonpsychiatric medications, including warfarin and oral contraceptives.¹⁵

Other anticonvulsants

For unclear reasons, anticonvulsants are often hepatic enzyme inducers. Phenobarbitol, primidone, and phenytoin have been associated with reduced plasma levels of numerous drugs.¹⁶ For example, phenytoin has been reported to increase clearance of the atypical antipsychotic quetiapine. In one report, phenytoin cessation resulted in a 24-fold increase in plasma quetiapine levels. Similarly, carbamazepine cessation increased quetiapine plasma levels 14-fold.¹⁷

Oxcarbazepine. Oxcarbazepine is a newer anticonvulsant—a keto-analogue of carbamazepine—that offers improved safety in overdose, no cardiotoxic effect, and no known risk of agranulocytosis. Like older anticonvulsants, oxcarbazepine is being used to treat mood disorders.