Get to Know an Enzyme: CYP1A2

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.

Table 1

CYP1A2 Substrates

Alosetron (Lotronex)

Caffeine

Clozapine (Clozaril)

Flutamide (Eulexin)

Frovatriptan (Frova)

Melatonin

Mexiletine (Mexitil)

Mirtazapine (Remeron)

Olanzapine (Zyprexa)

Ramelteon (Rozerem)

Rasagiline (Azilect)

Ropinirole (Requip)

Tacrine (Cognex)

Theophylline

Tizanidine (Zanaflex)

Triamterene (Dyrenium)

Zolmitriptan (Zomig)

The cytochrome P450 enzymesare found primarily in the liver,although some (eg, CYP3A4) arealso found in substantial amounts inthe intestine. They are involved in themetabolism of most medications andare the mechanism by which mostpharmacokinetic drug interactionsoccur. Cytochrome P450 3A4 (CYP3A4)is the superstar; it gets attentionbecause a majority of drugs are metabolizedby CYP3A4. Other importantCYP450 enzymes include CYP1A2,CYP2C9, CYP2C19, and CYP2D6. Herewe will focus on a rising star: CYP1A2.

CYP1A2 Substrates

The importance of CYP1A2 for druginteractions has been increasing overthe past decade due to the growingnumber of drugs metabolized by thisenzyme.¹ Drugs metabolized by CYP1A2are called CYP1A2 substrates.

CYP1A2 Inhibitors

Table 2

CYP1A2 Inhibitors

Artemisinin

Atazanavir (Reyataz)

Cimetidine (Tagamet)

Ciprofloxacin (Cipro)

Enoxacin

Ethinyl Estradiol

Fluvoxamine

Mexiletine

Tacrine (Cognex)

Thiabendazole

Zileuton (Zyflo)

Drugs that inhibit CYP1A2 will predictablyincrease the plasma concentrationsof the medications listed inTable 1, and in some cases adverseoutcomes will occur. Of particular noteis fluvoxamine, which is a potentCYP1A2 inhibitor and also inhibitsother CYP450 enzymes, such asCYP2C19, CYP3A4, and to some extentCYP2C9. Thus, fluvoxamine may preventother metabolic pathways fromcompensating for the CYP1A2 inhibition.The fluoroquinolone antibiotics,enoxacin and ciprofloxacin, also substantiallyinhibit CYP1A2.

CYP1A2 Inducers

Table 3

CYP1A2 Inducers

Barbiturates

Cruciferous vegetables

Grilled meat

Carbamazepine (eg, Tegretol)

Primidone

Rifampin (eg, Rifadin)

Smoking

Other drugs may stimulate CYP1A2,and they may reduce the efficacy ofCYP1A2 substrates. Of particular noteis cigarette smoking, which can substantiallyincrease CYP1A2 activity.2Thus, smoking may reduce the efficacyof any of the CYP1A2 substrates. Forexample, it has been known for manyyears that smoking substantiallyincreases theophylline dosage requirements.More recently, smoking hasbeen shown to reduce the serum concentrationsand efficacy of the atypicalantipsychotics, clozapine and olanzapine.

Important Drug Interactions Involving CYP1A2

Some CYP1A2 interactions have limitedclinical importance; for example,most patients can withstand an elevatedcaffeine concentration due tociprofloxacin without significant adverseconsequences. Others, however,can be serious. Historically, the mostimportant CYP1A2 drug interactionswere probably severe theophylline toxicitydue to concurrent use of theophyllinewith CYP1A2 inhibitors suchas ciprofloxacin or fluvoxamine. Thesestill occur occasionally, even withreduced use of theophylline, but themany newer CYP1A2 substrates nowpresent drug-interaction problemswith CYP1A2 inhibitors. For example,tizanidine plasma concentrationsincreased over 30-fold when thepotent CYP1A2 inhibitor fluvoxaminewas given concurrently.

Assessing CYP1A2 Activity in Patients

For some CYP450 enzymes such asCYP2D6, genetic factors dictate mostof the activity of the enzyme, and genotypingof patients may be useful. This isnot true for CYP1A2, however, wherethe activity of the enzyme is dictatedlargely by environmental, dietary, andother factors in addition to genetics.1 Inthis case, phenotyping is more useful,where, instead of genetic testing, aprobe compound is given to the patientand the actual enzyme activity is determined.One proposed phenotypingmethod for CYP1A2 is to obtain a salivasample following a test dose of caffeine.One drawback of such testing isthat the subject must abstain from coffee,many teas and soft drinks, andchocolate for a day or so before thetest.

Summary

The enzyme CYP1A2 increasingly isinvolved in drug interactions as newmedications metabolized by thisenzyme are released. Some of the substratesthat warrant particular attentionare theophylline, clozapine, olanzapine,and tizanidine. Some of themore potent CYP1A2 inhibitors includecimetidine, ciprofloxacin, enoxacin,and fluvoxamine. Among CYP1A2inducers, smoking is probably the mostimportant, but the usual enzyme inducerssuch as rifampin and barbituratescan also substantially increase CYP1A2activity.

References

• Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol. 2005;97:125-134.
• Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64:1917-1921.