drugINTERACTIONS: insights and observations Get …

1 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 metab-olized by importantCYP450 enzymes include CYP1A2,CYP2C9,CYP2C19,and will focus on a rising star: SubstratesThe importance of CYP1A2 for druginteractions has been increasing overthe past decade due to the growingnumber of drugs metabolized by metabolized by CYP1A2are called CYP1A2 InhibitorsDrugs that inhibit CYP1A2 will pre-dictably increase the plasma concen-trations of the medications listed inTable 1, and in some cases adverseoutcomes will occur.

2 Of particular noteis fluvoxamine, which is a potentCYP1A2 inhibitor and also inhibitsother CYP450 enzymes, such asCYP2C19,CYP3A4, and to some extentCYP2C9. Thus, fluvoxamine may pre-vent other metabolic pathways fromcompensating for the CYP1A2 inhibi-tion. The fluoroquinolone antibiotics,enoxacin and ciprofloxacin, also sub-stantially inhibit InducersOther drugs may stimulate CYP1A2,and they may reduce the efficacy ofCYP1A2 substrates. Of particular noteis cigarette smoking, which can sub-stantially increase CYP1A2 , smoking may reduce the efficacyof any of the CYP1A2 substrates. Forexample, it has been known for manyyears that smoking substantiallyincreases theophylline dosage require-ments.

3 More recently, smoking hasbeen shown to reduce the serum con-centrations and efficacy of the atypicalantipsychotics, clozapine and Drug InteractionsInvolving CYP1A2 Some CYP1A2 interactions have lim-ited clinical importance; for example,most patients can withstand an elevat-ed caffeine concentration due tociprofloxacin without significant ad-verse consequences. Others, however,can be serious. Historically, the mostimportant CYP1A2 drug interactionswere probably severe theophylline tox-icity due to concurrent use of theo-phylline with 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.

4 For example,tizanidine plasma concentrationsincreased over 30-fold when thepotent CYP1A2 inhibitor fluvoxaminewas given CYP1A2 Activity inPatientsFor some CYP450 enzymes such asCYP2D6, genetic factors dictate mostof the activity of the enzyme, and geno-typing of 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 case, phenotyping is more useful,where, instead of genetic testing, aprobe compound is given to the patientand the actual enzyme activity is deter-mined. One proposed phenotypingmethod for CYP1A2 is to obtain a sali-va sample following a test dose of drawback of such testing isthat the subject must abstain from cof-fee,many teas and soft drinks,andchocolate for a day or so before enzyme CYP1A2 increasingly isinvolved in drug interactions as newmedications metabolized by thisenzyme are released.

5 Some of the sub-strates that warrant particular atten-tion are theophylline, clozapine, olan-zapine, and tizanidine. Some of themore potent CYP1A2 inhibitors includecimetidine, ciprofloxacin, enoxacin,and fluvoxamine. Among CYP1A2inducers, smoking is probably the mostimportant, but the usual enzyme induc-ers such as rifampin and barbituratescan also substantially increase to Know an Enzyme: CYP1A2 John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD76nNovember 2007|Pharmacy Horn and Hansten are both pro-fessors of pharmacy at the Universityof Washington School of an electronic version of this arti-cle, including references if any, : insights and observationsFor a list of references, go to: lists of CYP1A2 substrates, inhibitors, and inducers, go to