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](#table 1) provides examples of drugs that interact with CYP enzymes and transporter systems. Table 1 also includes five other substances that intera…
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](#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](#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)
Table 1: CYP Enzyme- and Transporter System-Based Clinical Substrates, Inhibitors, or Inducers
How to use the filter and search functions in Table 1
To refine your search for interacting examples of drugs* in CYP-based metabolic- and transporter system-based drug interaction classes, use the filters (in the box below) and/or the search box (located below the filters and above the table of examples).
When using the search box, include the name of the drug substance rather than the name of the drug product or the proprietary name. For example, search for “atorvastatin” instead of “atorvastatin calcium tablets” or “LIPITOR.” The search ignores the following symbols: ., (, ), ‘, -, and /. Thus, when searching for “St. John’s wort,” you will obtain the correct results by typing “St. John’s wort” or “St. John s wort”, but not St. Johns wort”. If you are not sure of the spelling of the drug name, use Browse by Drug Name on the Drugs@FDA home page to find drug names in alphabetical order.
The filters and search box operate using an “and” function. This means the use of two or more filters or the combination of filters with the search box returns results that meet both criteria. For example, if you are searching for strong 2C19 inhibitors (use the CYP strong inhibitor filter and select “2C19” in the drop-down menu) and weak CYP 2B6 inhibitors (use the CYP weak inhibitor filter and select “2B6” in the drop-down menu) the results will:
- Only include drugs that are both CYP strong 2C19 inhibitors AND CYP 2B6 weak inhibitors
- Not include drugs that are CYP strong 2C19 inhibitors only
- Not include drugs that are CYP 2B6 weak inhibitors only
Thus, if you are searching for strong 2C19 inhibitors OR weak CYP 2B6 inhibitors, conduct your search for each separately.
* Although this website focuses on examples of drugs in CYP-based metabolic- and transporter system-based drug interaction classes, St. John’s wort (a dietary supplement), curcumin (a supplement), diosmin (a supplement), smoking tobacco, and grapefruit juice (a food) are also included in this listing.
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.
CYP strong inhibitor
CYP moderate inhibitor
CYP weak inhibitor
CYP strong inducer
CYP moderator inducer
CYP weak inducer
CYP sensitive substrate
CYP moderate sensitive substrate
Transporter inhibitor
Transporter substrate
| 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 | |||||||||
| adagrasib | 3A strong inhibitor | |||||||||
| adefovir1 | OAT1 substrate | |||||||||
| alfentanil | 3A sensitive substrate | |||||||||
| allopurinol | 1A2 weak inhibitor | |||||||||
| alosetron | 1A2 sensitive substrate | |||||||||
| alprazolam | 3A moderate sensitive substrate | |||||||||
| amiodarone | 2C9 moderate inhibitor | 2D6; 3A weak inhibitor | P-gp inhibitor | |||||||
| apalutamide | 3A strong inducer | 2C19 moderate inducer | 2C9 weak inducer | |||||||
| aprepitant | 2C9 weak inducer | 3A moderate sensitive substrate | ||||||||
| aprepitant | 3A moderate inhibitor | |||||||||
| armodafinil | 3A weak inducer | |||||||||
| atazanavir and ritonavir | OATP1B1; OATP1B3 inhibitor | |||||||||
| atomoxetine | 2D6 sensitive substrate | |||||||||
| atorvastatin | 3A moderate substrate | OATP1B1; OATP1B3 substrate | ||||||||
| avanafil | 3A sensitive substrate | |||||||||
| baricitinib | OAT3 substrate | |||||||||
| bosentan | 3A moderate inducer | OATP1B1; OATP1B3 substrate | ||||||||
| Brigatinib | 3A moderately sensitive substrate | |||||||||
| budesonide | 3A sensitive substrate | |||||||||
| bumetanide | OAT3 substrate | |||||||||
| bupropion2 | 2D6 strong inhibitor | 2B6 sensitive substrate | ||||||||
| buspirone | 3A sensitive substrate | |||||||||
| caffeine | 1A2 sensitive substrate | |||||||||
| capmatinib | 1A2 moderate inhibitor | P-gp; BCRP inhibitor | ||||||||
| carbamazepine | 2B6; 3A strong inducer | 2C9 weak inducer | ||||||||
| cefaclor | OAT3 substrate | |||||||||
| ceftizoxime | OAT3 substrate | |||||||||
| celecoxib3 | 2D6 weak inhibitor | 2C9 sensitive substrate | ||||||||
| cenobamate4 | 2C19 moderate inhibitor | CYP3A moderate inducer b | ||||||||
| ceritinib | 3A strong inhibitor | 2C9 weak inhibitor | ||||||||
| chlorzoxazone | 3A weak inhibitor | |||||||||
| cilostazol | 3A weak inhibitor | |||||||||
| cimetidine | 3A; 1A2; 2D6 weak inhibitor | OCT2; MATE1; MATE2-K inhibitor | ||||||||
| cinacalcet | 2D6 moderate inhibitor | |||||||||
| ciprofloxacin | 1A220; 3A moderate inhibitor | OAT1; OAT3 substrate | ||||||||
| clarithromycin | 3A strong inhibitor | P-gp; OATP1B1; OATP1B3 inhibitor | ||||||||
| clobazam | 2D6 weak inhibitor | |||||||||
| clopidogrel | 2C8 moderate inhibitor | 2B6 weak inhibitor | ||||||||
| clotrimazole | 3A weak inhibitor | |||||||||
| clozapine | 1A2 moderate sensitive substrate | |||||||||
| cobicistat | 3A strong inhibitor | 2D6 weak inhibitor | P-gp inhibitor | |||||||
| colchicine | 3A moderate sensitive substrate | |||||||||
| conivaptan | 3A moderate inhibitor5 | 3A sensitive substrate | ||||||||
| crizotinib | 3A moderate inhibitor | |||||||||
| curcumin | BCRP inhibitor | |||||||||
| cyclosporine | 3A weak inhibitor | P-gp; BCRP; OATP1B1; OATP1B3 inhibitor | ||||||||
| dabigatran etexilate | P-gp substrate | |||||||||
| dabrafenib | 3A moderate inducer | 2C9 weak inducer | ||||||||
| darifenacin | 3A sensitive substrate | |||||||||
| darolutamide | BCRP; OATP1B1; OATP1B3 inhibitor | |||||||||
| darunavir6 | 3A sensitive substrate | |||||||||
| dasatinib | 3A sensitive substrate | |||||||||
| deferasirox | 2C8 moderate inhibitor | |||||||||
| desipramine | 2D6 sensitive substrate | |||||||||
| desloratadine | 2C8 moderately sensitive substrate | |||||||||
| dextromethorphan | 2D6 sensitive substrate | |||||||||
| diazepam | 2C19 moderate sensitive substrate | |||||||||
| digoxin | P-gp substrate | |||||||||
| diltiazem7 | 3A moderate inhibitor | |||||||||
| diosmin | 2C9 weak inhibitor | |||||||||
| disulfiram | 2C9 weak inhibitor | |||||||||
| docetaxel | OATP1B1; OATP1B3 substrate | |||||||||
| dolutegravir | OCT2 inhibitor | |||||||||
| dronedarone | 3A moderate inhibitor | 3A sensitive substrate | P-gp inhibitor | |||||||
| duloxetine | 2D6 moderate inhibitor | 1A2 sensitive substrate | ||||||||
| edoxaban | P-gp substrate | |||||||||
| efavirenz | 3A; 2B6; 2C19 moderate inducer | 2B6 moderate sensitive substrate | ||||||||
| elagolix | 3A weak inducer | OATP1B1; OATP1B3 substrate | ||||||||
| eletriptan | 3A sensitive substrate | |||||||||
| eliglustat | 2D6 sensitive substrate | 3A moderate sensitive substrate | ||||||||
| eltrombopag | BCRP; OATP1B1; OATP1B3 inhibitor | |||||||||
| elvitegravir and ritonavir | 3A strong inhibitor | |||||||||
| Entrectinib | 3A weak inhibitor | 3A sensitive substrate | ||||||||
| enzalutamide | 3A strong inducer | 2C9; 2C19 moderate inducer | ||||||||
| eplerenone | 3A sensitive substrate | |||||||||
| erythromycin | 3A moderate inhibitor | P-gp inhibitor | ||||||||
| escitalopram | 2D6 weak inhibitor | |||||||||
| etravirine | 3A moderate inducer | |||||||||
| everolimus | 3A sensitive substrate | |||||||||
| famotidine | OAT3 substrate | |||||||||
| febuxostat | BCRP inhibitor | |||||||||
| felbamate | 2C19 moderate inhibitor | |||||||||
| felodipine | 3A sensitive substrate | |||||||||
| fexofenadine | OATP1B1; OATP1B3; P-gp substrate | |||||||||
| fluconazole | 2C19 strong inhibitor | 3A; 2C9 moderate inhibitor | ||||||||
| fluoxetine | 2C19; 2D6 strong inhibitor | |||||||||
| fluvastatin | 2C9 weak inhibitor | |||||||||
| fluvoxamine8 | 1A2; 2C19 strong inhibitor | 3A; 2C9; 2D6 weak inhibitor | ||||||||
| fosaprepitant | 3A 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 | 3A moderate inhibitor | |||||||||
| ibrutinib | 3A sensitive substrate | |||||||||
| idelalisib | 3A strong inhibitor | |||||||||
| imatinib | 3A moderate inhibitor | |||||||||
| imipramine | 2D6 moderate sensitive substrate | |||||||||
| indinavir6 | 3A sensitive substrate | |||||||||
| indinavir and ritonavir | 3A strong inhibitor | |||||||||
| isavuconazole | 3A moderate inhibitor | 2B6 weak inducer | 3A sensitive substrate | OCT2; MATE1; MATE2-K inhibitor | ||||||
| istradefylline | 3A weak inhibitor | |||||||||
| itraconazole | 3A strong inhibitor | P-gp inhibitor | ||||||||
| ivabradine | 3A sensitive substrate | |||||||||
| ivacaftor | 3A weak inhibitor | |||||||||
| ivosidenib10 | 3A strong inducer | |||||||||
| ketoconazole | 3A strong inhibitor | P-gp inhibitor | ||||||||
| labetalol | 2D6 weak inhibitor | |||||||||
| lansoprazole11 | 2C19 moderate sensitive substrate | |||||||||
| lapatinib | P-gp inhibitor | |||||||||
| Larotrectinib | 3A weak inhibitor | 3A moderately sensitive substrate | ||||||||
| Lazertinib | 3A weak inhibitor | BCRP inhibitor | ||||||||
| lemborexant | 2B6 weak inducer | 3A sensitive substrate | ||||||||
| lomitapide | 3A weak inhibitor | 3A sensitive substrate | ||||||||
| Loperamide | 2C8 and 3A moderately sensitive substrate | P-gp transporter substrate | ||||||||
| lopinavir and ritonavir | 3A strong inhibitor | P-gp; OATP1B1; OATP1B3 inhibitor | ||||||||
| lorcaserin | 2D6 moderate inhibitor | |||||||||
| lorlatinib | 3A moderate inducer | 2B6; 2C9 weak inducer | ||||||||
| lovastatin | 3A sensitive substrate | OATP1B1 substrate | ||||||||
| lumacaftor and ivacaftor | 3A strong inducer | |||||||||
| lurasidone | 3A sensitive substrate | |||||||||
| maraviroc | 3A 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 | 3A sensitive substrate | |||||||||
| mirabegron | 2D6 moderate inhibitor | |||||||||
| mitotane | 3A strong inducer | |||||||||
| mobocertinib | 3A weak inducer | 3A sensitive substrate | ||||||||
| modafinil12 | 3A weak inducer | |||||||||
| montelukast | 2C8 moderate sensitive substrate | |||||||||
| naloxegol | 3A sensitive substrate | |||||||||
| nebivolol | 2D6 sensitive substrate | |||||||||
| nefazodone | 3A strong inhibitor | |||||||||
| nelfinavir | 3A strong inhibitor | |||||||||
| nevirapine | 2B6 weak inducer | |||||||||
| nisoldipine | 3A 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) | 3A strong inhibitor | |||||||||
| paroxetine | 2D6 strong inhibitor | |||||||||
| peginterferon alpha-2a | 1A2 weak inhibitor | |||||||||
| penicillin G | OAT3 substrate | |||||||||
| perphenazine | 2D6 sensitive substrate | |||||||||
| pexidartinib | 3A moderate inducer | |||||||||
| phenobarbital | 3A moderate inducer | |||||||||
| phenytoin | 3A strong inducer | 1A2; 2C19 moderate inducer | 2C9 moderate sensitive substrate | |||||||
| pimozide | 2D6 and 3A moderately sensitive substrate | |||||||||
| pioglitazone | 2C8 moderate sensitive substrate | |||||||||
| piperine | 2C9 moderate inhibitor | 1A2 weak inhibitor | ||||||||
| pirfenidone | 1A2 moderate sensitive substrate | |||||||||
| Pirtobrutinib | 2C8 moderate inhibitor | 3A and 2C19 weak inhibitor | BCRP and P-gp transporters inhibitor | |||||||
| pitavastatin | OATP1B1; OATP1B3 substrate | |||||||||
| posaconazole | 3A strong inhibitor | |||||||||
| Pralsetinib | 3A moderately sensitive substrate | |||||||||
| pravastatin | OATP1B1; OATP1B3 substrate | |||||||||
| primidone | 3A 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 | 3A sensitive substrate | |||||||||
| quinidine | 2D6 strong inhibitor | P-gp inhibitor | ||||||||
| R-venlafaxine | 2D6 sensitive substrate | |||||||||
| rabeprazole | 2C19 moderate sensitive substrate | |||||||||
| ramelteon | 1A2 sensitive substrate | |||||||||
| ranitidine | 3A weak inhibitor | |||||||||
| ranolazine | 3A weak inhibitor | P-gp ; OCT2; MATE1; MATE2-K inhibitor | ||||||||
| repaglinide | 2C8 sensitive substrate | OATP1B1; OATP1B3 substrate | ||||||||
| resmetirom | 2C8 weak inhibitor | 2C8 moderately sensitive substrate | BCRP and OATP1B transporters inhibitor | OATP1B transporter substrate | ||||||
| Repotrectinib | 3A moderate inducer | 3A sensitive substrate | ||||||||
| rifampin | 3A; 2C19 strong inducer | 1A2, 2B6; 2C8; 2C9 moderate inducer | OATP1B113; OATP1B313 inhibitor | |||||||
| rilpivirine | 3A moderate sensitive substrate | |||||||||
| ritonavir 14, 15, 16 | 3A strong inhibitor | 2B6; 2C9; 2C19 weak inducer | ||||||||
| rivaroxaban | 3A moderate sensitive substrate | |||||||||
| rolapitant17 | 2D6 moderate inhibitor | BCRP inhibitor | ||||||||
| rosiglitazone | 2C8 moderate sensitive substrate | |||||||||
| rosuvastatin | BCRP; OATP1B1; OATP1B3 substrate | |||||||||
| rufinamide | 3A weak inducer | |||||||||
| S-mephenytoin | 2C19 sensitive substrate | |||||||||
| S-venlafaxine | 2D6 moderate sensitive substrate | |||||||||
| saquinavir6 | 3A sensitive substrate | |||||||||
| saquinavir and ritonavir | 3A strong inhibitor | P-gp inhibitor | ||||||||
| selexipag 21 | 2C8 sensitive substrate | |||||||||
| Selpercatinib | 2C8 moderate inhibitor | 3A weak inhibitor | 3A moderately sensitive substrate | |||||||
| sertraline | 2D6 weak inhibitor | |||||||||
| sevabertinib | 3A weak inhibitor | 3A moderately sensitive substrate | ||||||||
| sildenafil | 3A sensitive substrate | |||||||||
| simvastatin | 3A sensitive substrate | OATP1B1; OATP1B3 substrate | ||||||||
| sirolimus | 3A sensitive substrate | |||||||||
| Sofosbuvir and Velpatasvir and Voxilaprevir | P-gp; BCRP; OATP1B1; OATP1B3 inhibitor | |||||||||
| sotorasib | 3A moderate inducer | |||||||||
| St. John’s wort18 | 3A strong inducer | |||||||||
| sulfasalazine | BCRP substrate | |||||||||
| tacrolimus | 3A sensitive substrate | |||||||||
| tadalafil | 3A moderate sensitive substrate | |||||||||
| taletrectinib | 3A moderately sensitive substrate | |||||||||
| tasimelteon | 1A2 sensitive substrate | |||||||||
| Tazemetostat | 2C8 weak inhibitor | 3A weak inducer | 3A moderately sensitive substrate | |||||||
| telithromycin | 3A 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 | 3A weak inhibitor | 3A sensitive substrate | ||||||||
| ticlopidine | 2C19 strong inhibitor | 2B6 weak inhibitor | ||||||||
| tipranavir6 | 3A sensitive substrate | |||||||||
| tipranavir and ritonavir | 3A strong inhibitor | |||||||||
| tizanidine | 1A2 sensitive substrate | |||||||||
| tobacco (smoking) | 1A2 moderate inducer | |||||||||
| tolbutamide | 2C9 moderate sensitive substrate | |||||||||
| tolterodine | 2D6 sensitive substrate | |||||||||
| tolvaptan | 3A sensitive substrate | |||||||||
| tramadol | 2D6 moderate sensitive substrate | |||||||||
| triazolam | 3A sensitive substrate | |||||||||
| trimethoprim | 2C8 weak inhibitor | MATE1; MATE2-K inhibitor | ||||||||
| trimipramine | 2D6 moderate sensitive substrate | |||||||||
| tucatinib | 3A strong inhibitor | 2C8 weak inhibitor | 2C8 moderately sensitive substrate | P-gp transporter inhibitor | ||||||
| vandetanib | MATE1; MATE2-K inhibitor | |||||||||
| vardenafil | 3A sensitive substrate | |||||||||
| vemurafenib | 1A2 moderate inhibitor | 2D6 weak inhibitor | 3A weak inducer | |||||||
| venetoclax | 3A sensitive substrate | |||||||||
| verapamil | 3A moderate inhibitor | P-gp inhibitor | ||||||||
| voriconazole | 3A strong inhibitor | 2C19 moderate inhibitor | 2B6; 2C9; weak inhibitor | 2C19 moderate sensitive substrate | ||||||
| warfarin19 | 2C9 moderate sensitive substrate | |||||||||
| zanubrutinib | 3A weak inducer | |||||||||
| zileuton | 1A2 weak inhibitor | |||||||||
| zongertinib | BCRP 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
20Ciprofloxacin is generally classified a moderate CYP 1A2 inhibitor based on totality of evidence; however, it can sometimes behave like a strong inhibitor (i.e., increase AUC more than 5-fold) when it interacts with certain CYP 1A2 substrates that are considered highly sensitive (e.g., tizanidine).
21Selexipag is a prodrug. it is the selexipag active metabolite ACT-333679 that is a sensitive substrate of CYP2C8. Selexipag and ACT-333679 are also substrates of OATP1B transporter