Table 2
Common minor cytochrome P450 (CYP) 1A2 substrates
| Drug | Class |
|---|---|
| Acetaminophen3-9 | Analgesic |
| Almotriptan6 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Amitriptyline3-7,9-11 | Tricyclic antidepressant |
| Asenapine9 | Second-generation antipsychotic |
| Carvedilol5-7 | β and α adrenergic blocking activity |
| Chlorpromazine3,4,7-9,11 | First-generation antipsychotic |
| Chlorzoxazone4,7 | Skeletal muscle relaxant |
| Clopidogrel5 | Antiplatelet |
| Desipramine4,7,10,11 | Tricyclic antidepressant |
| Diazepam4,7,9,10 | Benzodiazepine |
| Diclofenac5,7 | Nonsteroidal anti-inflammatory drug |
| Diphenhydramine6 | Antihistamine |
| Febuxostat5 | Xanthine oxidase inhibitor |
| Fluphenazine3,9 | First-generation antipsychotic |
| Frovatriptan3 | Antimigraine: serotonin 1 agonist |
| Haloperidol3,4,6,8,9 | First-generation antipsychotic |
| Imipramine3,4,6-11 | Tricyclic antidepressant |
| Maprotiline6 | Tetracyclic antidepressant |
| Melatonin3,4,6,7 | Sleep-regulating hormone |
| Metoclopramide3 | Antiemetic: prokinetic gastrointestinal agent |
| Nabumetone6 | Nonsteroidal anti-inflammatory drug |
| Naproxen3,4,6,7 | Nonsteroidal anti-inflammatory drug |
| Naratriptan10 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Nicardipine3,7 | Calcium channel blocker |
| Nortriptyline4,6,7,9-11 | Tricyclic antidepressant |
| Ondansetron3,4,6,7 | Antiemetic: serotonin 3 antagonist |
| Palonosetron5 | Antiemetic: serotonin 3 antagonist |
| Perphenazine3,7 | First-generation antipsychotic |
| Progesterone5,7 | Progestin |
| Propofol4,6,7 | General anesthetic |
| Ranitidine5,7 | H2 antagonist |
| Rivastigmine10 | Acetylcholinesterase inhibitor |
| Selegiline6,7 | Antiparkinson: type B monoamine oxidase inhibitor |
| Thioridazine3,4,6 | First-generation antipsychotic |
| Tizanidine3-6 | Skeletal muscle relaxant: α-2 adrenergic agonist |
| Trazodone6,9 | Serotonin reuptake inhibitor and antagonist |
| Triamterene6 | Diuretic: potassium sparing |
| Verapamil3,4,6,7,10 | Calcium channel blocker |
| Warfarin3,4,6-10 | Anticoagulant: coumarin derivative |
| Zileuton3,4,6,7 | Asthma agent: 5-lipoxygenase inhibitor |
| Ziprasidone3,4 | Second-generation antipsychotic |
| Zolmitriptan3,6,7 | Antimigraine: serotonin 1B, 1D receptor agonist |
| Zolpidem4,6,7 | Nonbenzodiazepine hypnotic |
| Several classes of CYP1A2 substrates are not included and may cause toxicity with smoking cessation or require dosage increases in tobacco smokers (eg, antiarrhythmic, antifungal, antimalarial, antineoplastic, antiretroviral and anthelmintic agents and the antibiotic quinolone). Clinicians should be most concerned about drugs with a narrow therapeutic index and those that may be toxic with smoking cessation (eg, bleeding from warfarin and clopidogrel; high serum concentrations of caffeine, clozapine, olanzapine, propranolol, and theophylline) | |
SGA such as clozapine and olanzapine are major substrates of CYP1A2 and dosages may need to be adjusted when smoking status changes, depending on clinical efficacy and adverse effects.10,14,15 Maximum induction of clozapine and olanzapine metabolism may occur with 7 to 12 cigarettes per day and smokers may have 40% to 50% lower serum concentrations compared with nonsmokers.14 When a patient stops smoking, clozapine and olanzapine dosages may need to be reduced by 30% to 40% (eg, a stepwise 10% reduction in daily dose until day 4) to avoid elevated serum concentrations and risk of toxicity symptoms.15
Tobacco smokers can tolerate high daily intake of caffeinated beverages because of increased metabolism and clearance of caffeine, a major substrate of CYP1A2.11 When patients stop smoking, increased caffeine serum concentrations may cause anxiety, irritability, restlessness, insomnia, tremors, palpitations, and tachycardia. Caffeine toxicity also can mimic symptoms of nicotine withdrawal; therefore, smokers should be advised to reduce their caffeine intake by half to avoid adverse effects when they stop smoking.10,11
Adjusting dosing
Factors such as the amount and frequency of tobacco smoking, how quickly CYP1A2 enzymes change when starting and stopping smoking, exposure to secondhand smoke, and other concomitant drugs contribute to variability in pharmacokinetic drug interactions. Heavy smokers (≥30 cigarettes per day) should be closely monitored because variations in drug serum concentrations may be affected significantly by changes in smoking status.4,9,11 Dosage reductions of potentially toxic drugs should be done immediately when a heavy tobacco user stops smoking.10 For CYP1A2 substrates with a narrow therapeutic range, a conservative approach is to reduce the daily dose by 10% per day for several days after smoking cessation.11,16 The impact on drug metabolism may continue for weeks to a month after the person stops smoking; therefore, there may be a delay until CYP1A2 enzymes return to normal hepatic metabolism.4,8,9,15 In most situations, smoking cessation reverses induction of hepatic CYP1A2 enzymes back to normal metabolism and causes serum drug concentrations to increase.10 Because secondhand smoke induces hepatic CYP1A2 enzymes, those exposed to smoke may have changes in drug metabolism due to environmental smoke exposure.11
Tobacco smokers who take medications and hormones that are metabolized by CYP1A2 enzymes should be closely monitored because dosage adjustments may be necessary when they start or stop smoking cigarettes. An assessment of CYP drug interactions and routine monitoring of efficacy and/or toxicity should be done to avoid potential adverse effects from medications and to determine if changes in dosages and disease state management are required.
Related Resources
- Rx for Change. Drug interactions with smoking. http://smokingcessationleadership.ucsf.edu/interactions.pdf.
- Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365(13):1222-1231.
Drug Brand Names
- Albuterol/ipratropium • Combivent
- Almotriptan • Axert
- Alosetron • Lotronex
- Aminophylline • Phyllocontin, Truphylline
- Amitriptyline • Elavil
- Amlodipine • Norvasc
- Asenapine • Saphris
- Betaxolol • Kerlone
- Carbamazepine • Carbatrol, Tegretol
- Carvedilol • Coreg
- Chlorpromazine • Thorazine
- Chlorzoxazone • Parafon Forte
- Cimetidine • Tagamet
- Ciprofloxacin • Cipro
- Clomipramine • Anafranil
- Clopidogrel • Plavix
- Clozapine • Clozaril
- Cyclobenzaprine • Flexeril
- Desipramine • Norpramin
- Diazepam • Valium
- Diclofenac • Voltaren
- Diphenhydramine • Benadryl
- Doxepin • Silenor, Sinequan
- Duloxetine • Cymbalta
- Estradiol • Estrace
- Estrogens (conjugated) • Cenestin, Premarin
- Estropipate • Ogen
- Febuxostat • Uloric
- Fluoxetine • Prozac
- Fluphenazine • Prolixin
- Fluvoxamine • Luvox
- Frovatriptan • Frova
- Guanabenz • Wytensin
- Haloperidol • Haldol
- Imipramine • Tofranil
- Maprotiline • Ludiomil
- Metoclopramide • Reglan
- Mirtazapine • Remeron
- Nabumetone • Relafen
- Naratriptan • Amerge
- Nicardipine • Cardene
- Nifedipine • Adalat, Procardia
- Nortriptyline • Aventyl, Pamelor
- Olanzapine • Zyprexa
- Omeprazole • Prilosec
- Ondansetron • Zofran
- Palonosetron • Aloxi
- Perphenazine • Trilafon
- Pimozide • Orap
- Primidone • Mysoline
- Progesterone • Prometrium
- Propofol • Diprivan
- Propranolol • Inderal
- Ramelteon • Rozerem
- Ranitidine • Zantac
- Rasagiline • Azilect
- Rifampin • Rifadin, Rimactane
- Riluzole • Rilutek
- Rivastigmine • Exelon
- Ropinirole • Requip
- Selegiline • Eldepryl, EMSAM, others
- Theophylline • Elixophyllin
- Thioridazine • Mellaril
- Thiothixene • Navane
- Tizanidine • Zanaflex
- Trazodone • Desyrel, Oleptro
- Triamterene • Dyrenium
- Trifluoperazine • Stelazine
- Verapamil • Calan, Verelan
- Warfarin • Coumadin, Jantoven
- Zileuton • Zyflo
- Ziprasidone • Geodon
- Zolmitriptan • Zomig
- Zolpidem • Ambien, Edluar