Evidence-Based Reviews

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

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

References

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Oxcarbazepine has been described as exhibiting “mild induction” of hepatic enzymes.¹⁸ The drug’s manufacturer reports that the agent can induce the 3A4 hepatic enzyme, reduce levels of oral contraceptives by 50%, and decrease calcium channel blocker levels by 28%.¹⁶ In two patients recently treated by the author:

adding oxcarbazepine, 600 mg bid, to the regimen of a male patient, age 46, with schizophrenia and obsessive-compulsive disorder resulted in a 100% reduction in the plasma level of clomipramine.
adding oxcarbazepine, 600 mg in the morning and 900 mg at bedtime, to the regimen of a woman, age 44, with bipolar disorder led to a 71% decrease in the plasma level of valproate.

Both patients exhibited some worsening of psychiatric symptoms after the inducing agent was added. More widespread use of oxcarbazepine for epilepsy, mood disorders, and perhaps other indications will define its hepatic enzyme-inducing effect more clearly.

Topiramate. Topiramate—which is used as an antiepileptic and to treat mood disorders—has been shown to decrease digoxin levels by 11% and the estrogenic component of oral contraceptives by 30%. Topiramate may both induce and inhibit hepatic enzyme metabolism and has been associated with a 25% increase in phenytoin levels in some patients.

Other known inducers

Lesser-known hepatic enzyme inducers include chronic cigarette smoking,¹⁹ marijuana smoking,²⁰ chronic ethanol use,²¹ modafinil,²² St. John’s wort,²³ prednisone,¹⁶ dexamethasone,¹⁶ omeprazole,¹⁶ rifampin,¹⁶ and isoniazid.¹⁶ Unfortunately, the doses and duration required for induction are undocumented. The effect of these agents can only be detected by the astute clinician or perhaps by measuring plasma levels of co-prescribed drugs.

Among more than 20 known CYP450 isoenzymes, the six that metabolize most clinically useful medications are 1A2, 2C9, 2C19, 2D6, 2E1, and the 3A family. The 3A isoenzymes metabolize the widest range of drugs, so any agent that induces them is likely to have many interactions.

Inducing agents affect numerous specific enzymes (Table 3). For example:

cigarette smoking induces at least 1A2
carbamazepine and other anticonvulsants induce at least 3A4, 1A2, 2C9, 2C19, and 2D6
alcohol induces at least 3A4 and 2E1.

These agents may induce other enzymes, but the effect has not yet been demonstrated in vivo or in vitro.

The catalogue of hepatic enzymes, inducers, and specific enzymes and substrates (affected drugs) is poorly documented, inadequately studied, and difficult to commit to memory. It is much simpler to assume that any inducing agent in a patient’s regimen may lower plasma levels and alter the efficacy of co-administered drugs that are also metabolized by the liver.

Compensating for induction

A careful patient history and monitoring of clinical effect and plasma levels can compensate for the effects of hepatic enzyme inducers.⁴ Dosages of affected drugs may need to be adjusted to achieve desired therapeutic levels.

Table 3

HEPATIC INDUCERS¹, AFFECTED ISOENZYMES², AND SOME AFFECTED MEDICATIONS³

Hepatic enzyme inducer	CYP1A2	CYP2C19	CYP2C9	CYP2D6	CYP3A family	CYP2E1
Carbamazepine	Clozapine⁴ Amitriptyline Fluoxetine Haloperidol	Citalopram Diazepam Imipramine Fluoxetine	Warfarin	Risperidone Paroxetine Amphetamine Perphenazine	OCP⁵ Alprazolam Quetiapine
Oxcarbazepine	Clomipramine			Clomipramine Risperidone	OCP
Phenytoin	Clozapine	Diazepam			OCP Quetiapine
Phenobarbital				Haloperidol Paroxetine Fluvoxamine
Topiramate ⁶					OCP
Omeprazole	Clozapine	Phenytoin
Rifampin		Phenytoin	Fluoxetine
Prednisone					OCP
Dexamethasone				Paroxetine	OCP
Hypericum (St. John’s wort)					OCP Cyclosporine⁷ Haloperidol Pimozide
Ethanol (chronic)				Tricyclics Neuroleptics	Alprazolam Trazodone Zaleplon	Ethanol Acetaminophen⁸
Cigarette smoking	Haloperidol Clozapine
OCP: Oral contraceptives ¹ Only clinically relevant inducing agents listed ² Cited by manufacturer or in literature ³ Examples of drugs known to be affected ⁴ Induction effect known, concomitant use not advisable due to possible addictive agranulocytosis risk ⁵ Among numerous medications metabolized by 3A isoenzymes ⁶ Acts as an inducer but also inhibits isoenzyme 2C19 ⁷ St. John’s wort use has been associated with reduced cyclosporine levels and acute transplant rejection. ⁸ Chronic alcohol intake has been associated with accelerated acetaminophen metabolism and toxic metabolite levels.

For example, a patient of the author was receiving two inducing agents, carbamazepine and phenytoin, for comorbid medical disorders. He required daily oral doses of 80 mg of haloperidol to achieve a plasma level of 8 ng/ml (therapeutic range in psychosis believed to be 4 to 16 ng/ml).⁴ By comparison, haloperidol given at 10 mg/d yielded a plasma level of 7 ng/ml in a comparably aged patient receiving no enzyme-inducing agents.

When an inducing agent is halted during psychotropic treatment, expect higher plasma levels, side effects, or even toxicity related to the psychotropic. This medication effect is likely as the inducing agent is tapered, discontinued, and cleared from the body (across approximately 5.5 times its half-life), and the induction process is gradually reversed.

Cessation of inducing agents has amplified the effects of clozapine⁸ and tricyclic antidepressants.¹⁰ Anecdotally, the taper and cessation of oxcarbazepine in the author’s bipolar patient resulted in a 40% increase in plasma risperidone level and an 118% increase in valproic acid level, without any increase in the dosage of either psychotropic. At baseline, the patient’s risperidone plasma level was 58 ng/ml (all parent compound). After oxcarbazepine was tapered and discontinued across 1 month, a repeat measurement of risperidone yielded a higher total plasma level (76 ng/ml) but an altered parent drug-to-metabolite ratio (risperidone 68 ng/ml, metabolite 8 ng/ml). This suggests that induction reversal was incomplete 2 weeks after oxcarbazepine was discontinued.