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For Healthcare Professionals | FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems

Drug-drug interactions can lead to changes in systemic exposure (e.g., maximum concentration (Cmax), area under the concentration time curve (AUC), average steady state concentration (Cpss)) potentially resulting in adverse reactions (higher drug exposure) or loss of efficacy (lower drug exposure).

Cytochrome P-450 (CYP) enzymes are responsible for the metabolism of many drugs, and transporter systems allow for movement of many drugs across cell membranes.  Thus, these enzymes and systems are often implicated in drug-drug interactions because of their effect on a drug’s pharmacokinetics (e.g., drug exposure).

Table 1 provides examples of drugs that interact with CYP enzymes and transporter systems. Table 1 also includes five other substances that interact with CYP enzymes and transporter systems (i.e., St. John’s wort (a dietary supplement), curcumin (a supplement), diosmin (a supplement), tobacco (smoking) and grapefruit juice (a food)). These examples were evaluated and compiled by FDA as an optional resource for healthcare professionals to consult when reviewing information in the DRUG INTERACTIONS section of the approved U.S. Prescribing Information (PI) in clinical practice. Table 2 provides definitions of substrates, inhibitors, and inducers for CYP-based metabolism and Table 3 provides definitions of inhibitors and substrates for drug transporter systems.

The field of metabolic and transporter pharmacology is rapidly evolving, thus the examples in Table 1 are a guide and not considered a comprehensive list of all possible drugs and other substances (e.g., foods, including dietary supplements) that fit these categories. This website contains examples of drugs with CYP enzyme-based and transporter-based interactions but does not include drugs with other mechanisms leading to drug interactions (such as certain interactions affecting drug absorption (e.g., chelating agents, resin-based binders, and drugs that change gut pH), interactions affecting drug plasma protein binding, or pharmacodynamic interactions).

This website contains examples of drugs with CYP enzyme-based and transporter-based interactions but does not include drugs with other mechanisms leading to drug interactions (such as certain interactions affecting drug absorption (e.g., chelating agents, resin-based binders, and drugs that change gut pH), interactions affecting drug plasma protein binding, or pharmacodynamic interactions)

Table 1: CYP Enzyme- and Transporter System-Based Clinical Substrates, Inhibitors, or Inducers

Filter boxes to find examples of drugs and other substances within selected pathways

Use filters in this box or use the search box (“Search”) that is directly below to refine the results.

 

 

Drug or Other Substance

CYP Strg INH

CYP Mod INH

CYP WK INH

CYP Strg IND

CYP Mod IND

CYP WK IND

CYP SENS SUB

CYP Mod SENS SUB

TRNSP INH

TRNSP SUB

abiraterone   2D6  moderate  inhibitor                
acyclovir     1A2  weak  inhibitor              
adefovir1                   OAT1  substrate
alfentanil             3A4  sensitive  substrate      
allopurinol     1A2  weak  inhibitor              
alosetron             1A2  sensitive  substrate      
alprazolam               3A4  moderate sensitive  substrate    
amiodarone   2C9  moderate  inhibitor 2D6; 3A4  weak  inhibitor           P-gp  inhibitor  
apalutamide       3A4  strong  inducer 2C19  moderate  inducer 2C9  weak  inducer        
aprepitant           2C9  weak  inducer   3A4  moderate  sensitive  substrate    
aprepitant   3A4  moderate  inhibitor                
armodafinil           3A4  weak  inducer        
atazanavir and ritonavir                 OATP1B1; OATP1B3  inhibitor  
atomoxetine             2D6  sensitive  substrate      
atorvastatin               3A4  moderate  substrate   OATP1B1; OATP1B3  substrate
avanafil             3A4  sensitive  substrate      
baricitinib                   OAT3 substrate
bosentan         3A4  moderate  inducer         OATP1B1; OATP1B3  substrate
budesonide             3A4  sensitive  substrate      
bumetanide                   OAT3 substrate
bupropion2 2D6  strong  inhibitor           2B6  sensitive  substrate      
buspirone             3A4  sensitive  substrate      
caffeine             1A2  sensitive  substrate      
carbamazepine       2B6; 3A4   strong  inducer   2C9  weak  inducer        
cefaclor                   OAT3  substrate
ceftizoxime                   OAT3  substrate
celecoxib3     2D6  weak  inhibitor       2C9  sensitive  substrate      
cenobamate4   2C19 moderate inhibitor     CYP3A4 moderate inducer b          
ceritinib 3A4  strong  inhibitor   2C9 weak inhibitor              
chlorzoxazone     3A4  weak  inhibitor              
cilostazol     3A4  weak inhibitor              
cimetidine     3A4; 1A2; 2D6  weak inhibitor           OCT2; MATE1; MATE2-K  inhibitor  
cinacalcet   2D6  moderate inhibitor                
ciprofloxacin 1A2  strong inhibitor 3A4  moderate inhibitor               OAT1; OAT3  substrate
clarithromycin 3A4  strong  inhibitor               P-gp; OATP1B1; OATP1B3  inhibitor  
clobazam     2D6  weak  inhibitor              
clopidogrel   2C8  moderate  inhibitor 2B6  weak  inhibitor              
clotrimazole     3A4  weak  inhibitor              
clozapine               1A2  moderate sensitive substrate    
cobicistat 3A4  strong  inhibitor   2D6  weak  inhibitor           P-gp inhibitor  
colchicine               3A4  moderate  sensitive  substrate    
conivaptan   3A4  moderate  inhibitor5         3A4  sensitive  substrate      
crizotinib   3A4  moderate  inhibitor                
curcumin                 BCRP  inhibitor  
cyclosporine     3A4  weak  inhibitor           P-gp; BCRP; OATP1B1; OATP1B3  inhibitor  
dabigatran etexilate                   P-gp  substrate
dabrafenib         3A4 moderate inducer 2C9  weak  inducer        
darifenacin             3A4  sensitive  substrate      
darolutamide                 BCRP; OATP1B1; OATP1B3  inhibitor  
darunavir6             3A4  sensitive  substrate      
dasatinib             3A4  sensitive  substrate      
deferasirox   2C8  moderate  inhibitor                
desipramine             2D6  sensitive  substrate      
dextromethorphan             2D6  sensitive  substrate      
diazepam               2C19  moderate sensitive  substrate    
digoxin                   P-gp  substrate
diltiazem7   3A4  moderate  inhibitor                
diosmin     2C9  weak  inhibitor              
disulfiram     2C9  weak  inhibitor              
docetaxel                   OATP1B1; OATP1B3  substrate
dolutegravir                 OCT2 inhibitor  
dronedarone   3A4  moderate  inhibitor         3A4  sensitive  substrate   P-gp  inhibitor  
duloxetine   2D6  moderate  inhibitor         1A2  sensitive  substrate      
edoxaban                   P-gp  substrate
efavirenz         3A4; 2B6; 2C19  moderate  inducer     2B6  moderate sensitive  substrate    
elagolix           3A4  weak  inducer        OATP1B1; OATP1B3  substrate
eletriptan             3A4  sensitive  substrate      
eliglustat             2D6  sensitive  substrate 3A4  moderate sensitive  substrate    
eltrombopag                 BCRP; OATP1B1; OATP1B3  inhibitor  
elvitegravir and ritonavir 3A4  strong  inhibitor                  
enzalutamide       3A4  strong  inducer 2C9; 2C19  moderate  inducer          
eplerenone             3A4  sensitive  substrate      
erythromycin   3A4  moderate  inhibitor             P-gp inhibitor  
escitalopram     2D6  weak  inhibitor              
etravirine         3A4  moderate  inducer          
everolimus             3A4  sensitive  substrate      
famotidine                   OAT3  substrate
febuxostat                 BCRP inhibitor  
felbamate   2C19  moderate  inhibitor                
felodipine             3A4  sensitive  substrate      
fexofenadine                   OATP1B1; OATP1B3; P-gp  substrate
fluconazole 2C19  strong  inhibitor 3A4; 2C9  moderate  inhibitor                
fluoxetine 2C19; 2D6  strong  inhibitor                  
fluvastatin     2C9  weak  inhibitor              
fluvoxamine8 1A2; 2C19  strong  inhibitor   3A4; 2C9; 2D6  weak  inhibitor              
fosaprepitant     3A4  weak  inhibitor              
fostamatinib                 BCRP inhibitor  
furosemide                   OAT1; OAT3  substrate
gemfibrozil 2C8  strong  inhibitor               OAT3; OATP1B1; OATP1B3  inhibitor  
glimepiride               2C9  moderate sensitive substrate    
glyburide                   OATP1B1; OATP1B3  substrate
grapefruit juice9   3A4  moderate  inhibitor                
ibrutinib             3A4  sensitive  substrate      
idelalisib 3A4  strong  inhibitor                  
imatinib   3A4  moderate  inhibitor                
imipramine               2D6  moderate sensitive  substrate    
indinavir6             3A4  sensitive  substrate      
indinavir and ritonavir 3A4  strong  inhibitor                  
isavuconazole   3A4  moderate  inhibitor       2B6  weak  inducer 3A4  sensitive  substrate   OCT2; MATE1; MATE2-K  inhibitor  
istradefylline     3A4  weak  inhibitor              
itraconazole 3A4  strong  inhibitor               P-gp  inhibitor  
ivabradine             3A4  sensitive  substrate      
ivacaftor     3A4  weak inhibitor              
ivosidenib10       3A4 strong inducer             
ketoconazole 3A4  strong  inhibitor               P-gp  inhibitor  
labetalol     2D6  weak  inhibitor              
lansoprazole11               2C19  moderate sensitive  substrate    
lapatinib                 P-gp  inhibitor  
lemborexant           2B6  weak  inducer 3A4  sensitive  substrate      
lomitapide     3A4  weak  inhibitor       3A4  sensitive  substrate      
lopinavir and ritonavir 3A4  strong  inhibitor               P-gp; OATP1B1; OATP1B3   inhibitor  
lorcaserin   2D6  moderate inhibitor                
lorlatinib         3A4 moderate inducer 2B6; 2C9 weak inducer        
lovastatin             3A4  sensitive  substrate     OATP1B1  substrate
lumacaftor and ivacaftor       3A4  strong  inducer            
lurasidone             3A4  sensitive  substrate      
maraviroc             3A4  sensitive  substrate      
melatonin             1A2  sensitive  substrate      
metformin                   MATE1; MATE2-K; OCT2  substrate
methotrexate                   OAT3  substrate
methoxsalen   1A2  moderate inhibitor                
metoprolol               2D6  moderate sensitive  substrate    
mexiletine   1A2  moderate  inhibitor                
miconazole   2C9  moderate  inhibitor                
midazolam             3A4  sensitive  substrate      
mirabegron   2D6  moderate  inhibitor                
mitotane       3A4  strong  inducer            
mobocertinib           3A4  weak  inducer 3A4  sensitive  substrate      
modafinil12           3A4  weak  inducer        
montelukast               2C8  moderate sensitive  substrate    
naloxegol             3A4  sensitive  substrate      
nebivolol             2D6  sensitive  substrate      
nefazodone 3A4  strong  inhibitor                  
nelfinavir 3A4  strong  inhibitor                  
nevirapine           2B6  weak  inducer        
nisoldipine             3A4  sensitive  substrate      
nortriptyline               2D6 moderate sensitive substrate    
omeprazole     2C19  weak  inhibitor       2C19  sensitive  substrate      
oral contraceptives   1A2  moderate  inhibitor                
oseltamivir carboxylate1                   OAT3  substrate
paclitaxel                   OATP1B1; OATP1B3  substrate
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 3A4  strong  inhibitor                  
paroxetine 2D6  strong  inhibitor                  
peginterferon alpha-2a     1A2  weak  inhibitor              
penicillin G                   OAT3  substrate
perphenazine             2D6  sensitive  substrate      
pexidartinib         3A4 moderate inducer          
phenobarbital         3A4  moderate  inducer          
phenytoin       3A4  strong  inducer 1A2; 2C19  moderate  inducer     2C9  moderate sensitive  substrate    
pimozide               3A4  moderate sensitive  substrate    
pioglitazone               2C8  moderate sensitive  substrate    
piperine   2C9  moderate  inhibitor 1A2  weak  inhibitor              
pirfenidone               1A2  moderate sensitive  substrate    
pitavastatin                   OATP1B1; OATP1B3  substrate
posaconazole 3A4  strong  inhibitor                  
pravastatin                   OATP1B1; OATP1B3  substrate
primidone         3A4  moderate  inducer          
probenecid                 OAT1; OAT3  inhibitor  
propafenone               2D6  moderate sensitive  substrate P-gp  inhibitor  
propranolol               2D6  moderate sensitive  substrate    
pyrimethamine                 MATE1; MATE2-K inhibitor  
quetiapine             3A4  sensitive substrate      
quinidine 2D6  strong  inhibitor               P-gp  inhibitor  
R-venlafaxine             2D6  sensitive  substrate      
rabeprazole               2C19  moderate sensitive  substrate    
ramelteon             1A2  sensitive  substrate      
ranitidine     3A4  weak  inhibitor              
ranolazine     3A4  weak  inhibitor           P-gp ; OCT2; MATE1; MATE2-K    inhibitor  
repaglinide             2C8  sensitive  substrate     OATP1B1; OATP1B3  substrate
rifampin       3A4; 2C19  strong  inducer 1A2, 2B6; 2C8; 2C9  moderate  inducer       OATP1B113; OATP1B313  inhibitor  
rilpivirine               3A4  moderate sensitive  substrate    
ritonavir 14, 15, 16 3A4  strong  inhibitor         2B6; 2C9; 2C19  weak  inducer        
rivaroxaban               3A4  moderate sensitive  substrate    
rolapitant17   2D6 moderate inhibitor             BCRP inhibitor  
rosiglitazone               2C8  moderate sensitive  substrate    
rosuvastatin                   BCRP; OATP1B1; OATP1B3   substrate
rufinamide           3A4  weak  inducer        
S-mephenytoin             2C19  sensitive  substrate      
S-venlafaxine               2D6  moderate sensitive  substrate    
saquinavir6             3A4  sensitive  substrate      
saquinavir and ritonavir 3A4  strong  inhibitor               P-gp  inhibitor  
sertraline     2D6  weak  inhibitor              
sildenafil             3A4  sensitive  substrate      
simvastatin             3A4  sensitive  substrate     OATP1B1; OATP1B3  substrate
sirolimus             3A4  sensitive  substrate      
Sofosbuvir and Velpatasvir and Voxilaprevir                 P-gp; BCRP;  OATP1B1; OATP1B3 inhibitor  
sotorasib         3A4 moderate inducer          
St. John’s wort18       3A4  strong  inducer            
sulfasalazine                   BCRP  substrate
tacrolimus             3A4  sensitive  substrate      
tadalafil               3A4  moderate sensitive  substrate    
tasimelteon             1A2  sensitive  substrate      
telithromycin 3A4  strong  inhibitor                  
tenofovir1     2B6  weak  inhibitor             OAT1  substrate
terbinafine 2D6  strong  inhibitor                  
teriflunomide   2C8  moderate  inhibitor     1A2  moderate  inducer       BCRP;  OATP1B1 inhibitor; OAT3 inhibitor  
theophylline               1A2  moderate sensitive  substrate    
ticagrelor     3A4  weak  inhibitor       3A4  sensitive  substrate         
ticlopidine 2C19  strong  inhibitor   2B6  weak  inhibitor              
tipranavir6             3A4  sensitive  substrate      
tipranavir and ritonavir 3A4  strong  inhibitor                  
tizanidine             1A2  sensitive  substrate      
tobacco (smoking)         1A2  moderate  inducer          
tolbutamide               2C9  moderate sensitive  substrate    
tolterodine             2D6  sensitive  substrate      
tolvaptan             3A4  sensitive  substrate      
tramadol               2D6  moderate sensitive  substrate    
triazolam             3A4  sensitive  substrate      
trimethoprim     2C8  weak  inhibitor           MATE1; MATE2-K  inhibitor  
trimipramine               2D6  moderate sensitive  substrate    
vandetanib                 MATE1; MATE2-K  inhibitor  
vardenafil             3A4  sensitive  substrate      
vemurafenib   1A2 moderate inhibitor 2D6  weak  inhibitor     3A4  weak  inducer        
venetoclax             3A4  sensitive  substrate      
verapamil   3A4  moderate  inhibitor             P-gp  inhibitor  
voriconazole 3A4  strong  inhibitor 2C19  moderate inhibitor 2B6; 2C9;  weak inhibitor         2C19 moderate sensitive substrate    
warfarin19               2C9  moderate sensitive substrate    
zanubrutinib           3A4  weak  inducer        
zileuton      1A2 weak  inhibitor              

Table 2: Legend for Inhibitors, Inducers, and Substrates of CYP Enzymes

Inhibitor

Potency Category

Definitions of inhibitors for CYP-based metabolism

Strong Inhibitor

Drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold

Moderate Inhibitor

Drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥2-fold to < 5-fold

Weak Inhibitor

Drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥1.25-fold to <2-fold

Inducer

Potency Category

Definitions of inducers for CYP-based metabolism

Strong Inducer

Drugs that decrease the AUC of sensitive substrates of a given metabolic pathway by ≥80%

Moderate Inducer

Drugs that decrease the AUC of sensitive substrates of a given metabolic pathway by ≥50% to <80%

Weak Inducer

Drugs that decrease the AUC of sensitive substrates of a given metabolic pathway by ≥20% to <50%

Substrate

Potency Category

Definitions of substrate for CYP-based metabolism

Sensitive Substrate

Drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors of a given metabolic pathway

Moderate Sensitive Substrate

Drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong inhibitors of a given metabolic pathway

 

Table 3: Legend for Inhibitors and Substrates for Transporter Systems

Inhibitor

Transporter System

Definitions of inhibitors for drug transporter systems

P-gp

Drugs with evidence of in vitro inhibition and AUC fold-increase of dabigatran, digoxin or edoxaban ≥ 1.5 with co-administration

BCRP

Drugs with evidence of in vitro inhibition and AUC fold-increase of rosuvastatin or sulfasalazine ≥ 1.5-fold with co-administration

OATP1B1/OATP1B3

Drugs with evidence of in vitro inhibition and AUC fold-increase ≥2 for at least one of clinical substrates in Table 1 with co-administration

OAT1/OAT3

Drugs with evidence of in vitro inhibition and AUC fold-increase ≥1.5 for at least one of clinical substrates in Table 1 with co-administration

OCT2/MATE

Drugs with evidence of in vitro inhibition and AUC fold-increase of metformin ≥ 1.5 with co-administration

Substrate

Transporter System

Definitions of substrates for drug transporter systems

P-gp

Drugs with evidence of 1) in vitro transport; 2) not extensively metabolized in vivo; and AUC fold-increase ≥ 1.5 with itraconazole, verapamil or quinidine co-administration

BCRP

Drugs with evidence of in vitro transport and AUC fold-increase ≥2 with pharmacogenetic alteration of ABCG2 (421C>A)

OATP1B1/OATP1B3

Drugs with evidence of in vitro transport and AUC fold-increase ≥2 with rifampin (single dose) or cyclosporine A co-administration, or pharmacogenetic alteration of SLCO1B1 (521T>C)

OAT1/OAT3

Drugs with evidence of in vitro transport and AUC fold-increase ≥ 1.5 with probenecid co-administration and fraction of the dose excreted into urine as an unchanged drug ≥ 0.5

OCT2/MATEs

Drugs with evidence of in vitro transport and AUC fold-increase ≥1.5 with dolutegravir or pyrimethamine co-administration and fraction of dose excreted into urine as an unchanged drug ≥0.5

 

Footnotes

1These drugs are active moieties of their corresponding pro-drugs, adefovir dipivoxil, oseltamivir, tenofovir alafenamide fumarate (TAF), and tenofovir disoproxil fumarate (TDF). Those pro-drugs are substrates of P-gp.

2Bupropion itself is not a sensitive substrate. It is metabolized by multiple enzymes including CYP2B6 that is only responsible for the formation of hydroxybupropion, an active metabolite. Thus, the considerations of drug interactions with CYP2B6 modulators should take into account plasma concentration changes of both buproprion and hydroxybupropion.

3Listed based on pharmacogenetic studies.

4The classification is based on 200 mg daily dose. The effect potentially could be stronger at 400 mg/day.

5The classification is based on studies conducted with intravenously administered conivaptan.

6Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.

7Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 5-fold.

8Fluvoxamine increased the AUC of certain sensitive CYP3A substrates more than 2-fold (e.g., increased the AUC of buspirone 2.35-fold)

9The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or more commonly as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).

10Based on PBPK simulation

11S-lansoprazole is a sensitive substrate in CYP2C19 extensive metabolizer subjects.

12Based on effect of 200 mg/day modafinil. A higher dosage (400 mg/day) modafinil had larger induction effect on CYP3A.

13Single dose

14Ritonavir is approved for use in combination with other anti-HIV or anti-HCV drugs. Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of anti-HIV or anti-HCV combination regimens on CYP3A activities.

15Moderate inducer of CYP1A2 with dosage of 800 mg/day ritonavir (not with other anti-HIV drugs). Effect on CYP1A2 at lower dosages of ritonavir is unknown.

16Weak inducer of CYP2B6, CYP2C9, and CYP2C19. Classification is based on studies conducted with ritonavir itself (not with other anti-HIV drugs) at dosages of 100-200 mg/day, although larger effects have been reported in literature for high dosages of ritonavir.

17Intravenously administered rolapitant does not inhibit BCRP

18The effect of St. John’s wort varies widely and is preparation dependent.

19S-warfarin

 
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