Loss of enzyme induction: Ups and downs of a hidden drug-drug interaction
Patients on antipsychotics are at risk for adverse events
when an inducer is removed.
Table 2
Effects of CYP/PGP induction on atypical antipsychotics
| Antipsychotic | Metabolic pathways | Effect of induction |
|---|---|---|
| Aripiprazole | 2D6 and 3A4 convert aripiprazole to active metabolite dehydro-aripiprazole | 3A4 induction decreases maximum concentration of aripiprazole and metabolite by 70% |
| Clozapine | Multiple enzymes convert clozapine to N-desmethylclozapine; mean contributions of CYP 1A2, 2C19, 3A4, 2C9, and 2D6 are 30%, 24%, 22%, 12%, and 6%, respectively, with CYP 1A2 predominantly involved at low concentrations | Loss of smoking-related 1A2 induction results in 50% increase in serum levels |
| Olanzapine | Direct glucuronidation or 1A2-mediated oxidation to N-desmethlyolanzapine | Carbamazepine use increases clearance by 50%. Olanzapine concentration:dose ratio is about 5-fold lower in smokers (7.9 +/- 2.6) than in nonsmokers (1.56 +/- 1.1; P |
| Paliperidone | 59% excreted unchanged in urine; phase I metabolism accounts for ≤10% of drug clearance | Unlikely to significantly impact levels, but impact of PGP induction is unknown |
| Quetiapine | 3A4-mediated sulfoxidation to inactive metabolite is primary pathway, but numerous metabolites noted, with 1 active metabolite (norquetiapine) | Phenytoin increases clearance 5-fold |
| Risperidone | 2D6 converts risperidone to active metabolite 9-OH risperidone | In a drug interaction study of risperidone, 6 mg/d for 3 weeks, followed by 3 weeks of carbamazepine, active moiety concentration was decreased by about 50% |
| Ziprasidone | 3A4 (~1/3); aldehyde oxidase (~2/3) | Approximately 35% decrease in ziprasidone exposure by carbamazepine |
| CYP: cytochrome P450; PGP: P-glycoprotein | ||
| Source: Reference 21 | ||
Clinical considerations
In the absence of detailed data on antipsychotic metabolism, clinicians can make intelligent decisions regarding potential DDIs by:
- knowing the extent of induction by common offenders (such as carbamazepine or phenytoin) documented in the medication’s prescribing information or demonstrated through convincing case reports or case series
- memorizing the list of CYP 1A2 and CYP 3A4/PGP inducers.
Patients who may be susceptible to effects from loss of enzyme induction (including smokers receiving olanzapine or clozapine or others taking 3A4/PGP inducers) must be identified, and plans made for dosage adjustments if inducing agents are discontinued for a sufficient time (≥1 week) to result in downregulation of CYP or PGP activity. A slow taper of the antipsychotic over 1 to 2 weeks to the new target dose should compensate for loss of enzyme or PGP induction.
For newer antipsychotic medications with limited data, the proposed discontinuation of an inducer should, at the minimum, prompt a discussion between the psychiatrist and patient regarding the expected increase in serum antipsychotic levels and potential adverse effects that may result. Clinicians also must make every attempt to stay apprised of a patient’s current medications, bearing in mind that another provider may prescribe an inducer. Patients with schizophrenia always should be educated to contact the psychiatrist following any change in medication regimen, placing particular emphasis on the 1 or 2 medications that are known to be implicated in DDIs with the patient’s current antipsychotic.
- Flockhart DA. Drug interactions: Cytochrome P450 drug interaction table. Indiana University School of Medicine. 2007. https://medicine.iupui.edu/flockhart/table.htm.
- Cozza KL, Armstrong SC, Oesterheld JR. Concise guide to drug interaction principles for medical practice: Cytochrome P450s, UGTS, p-glycoproteins. Washington, DC: American Psychiatric Press, Inc; 2003.
- Aripiprazole • Abilify
- Bupropion • Wellbutrin
- Carbamazepine • Carbatrol, Tegretol
- Clozapine • Clozaril
- Divalproex • Depakote
- Efavirenz • Sustiva
- Lansoprazole • Prevacid
- Modafinil • Provigil
- Nevirapine • Viramune
- Olanzapine • Zyprexa
- Omeprazole • Prilosec
- Oxcarbazepine • Trileptal
- Paliperidone • Invega
- Pantoprazole • Protonix
- Phenobarbital • Barbita, Luminal, others
- Phenytoin • Dilantin
- Pioglitazone • Actos
- Quetiapine • Seroquel
- Rifampin • Rifadin, Rimactane
- Risperidone • Risperdal
- Ziprasidone • Geodon
Dr. Meyer receives grant/research support from the National Institute of Mental Health, Pfizer Inc., and the University of California. He is a consultant to Bristol-Myers Squibb, Organon, Vanda Pharmaceuticals, and Wyeth, and a speaker for AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, and Pfizer Inc.
Ms. Leckband reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
