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Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers


 CYP Enzymes

 In vitro

Table 1: Chemical inhibitors for in vitro experiments* (9/25/2006)

CYPInhibitor (1)
Preferred
Ki
(µM)
Inhibitor (1)
Acceptable
Ki
(µM)
1A2furafylline (2)0.6-0.73a -naphthoflavone0.01
2A6tranylcypromine
methoxsalen (2)
0.02-0.2
0.01-0.2
pilocarpine
tryptamine
4
1.7 (3)
2B6 
 
 
 3-isopropenyl-3-methyl diamantane (4)
2-isopropenyl-2-methyl adamantane (4)
sertraline
phencyclidine
triethylenethiophosphoramide (thiotepa)
clopidogrel
ticlopidine
2.2
5.3
3.2 (5)
10
4.8
0.5
0.2
2C8montelukast
quercetin
 
1.1
trimethoprim
gemfibrozil
rosiglitazone
pioglitazone
32
69-75
5.6
1.7
2C9sulfaphenazole

0.3

fluconazole
fluvoxamine
fluoxetine
7
6.4-19
18-41
2C19  ticlopidine
nootkatone
1.2
0.5
2D6quinidine0.027-0.4  
2E1  diethyldithiocarbamate
clomethiazole
diallyldisulfide
9.8-34
12
150
3A4/5ketoconazole
itraconazole
0.0037- 0.18
0.27, 2.3
azamulin
troleandomycin
verapamil
(6)
17
10, 24

* Note that this is not an exhaustive list which was created May 1, 2006.

  1. Substrates used for inhibition studies include: CYP1A2, phenacetin-o-deethylation, theophylline-N-demethylation; CYP2A6, coumarin-7-hydroxylation; CYP2B6, 7-pentoxyresorufin-O-depentylation, bupropion hydroxylation, 7-ethoxy-4-(trifluoromethyl)-coumarin O-deethylation, S-mephenytoin-N-demethylation; Bupropion-hydroxylation; CYP2C8, taxol 6-alpha-hydroxylation; CYP2C9, tolbutamide 4-methylhydroxylation, S-warfarin-7-hydroxylation, phenytoin 4-hydroxylation; 2CYP2C19, (S)-mephenytoin 4-hydroxylation CYP2D6, dextramethorphan O-demethylation, desbrisoquine hyddroxylase; CYP2E1, chlorzoxazone 6-hydroxylation, aniline 4-hydroxylase; CYP3A4/5, testosterone-6ß-hydroxylation, midazolam-1-hydroxylation; cyclosporine hydroxylase; nefedipine dehydrogenation.
  2. Furafylline and methoxsalen are mechanism-based inhibitors and should be pre-incubated before adding substrate.
  3. cDNA expressing microsomes from human lymphoblast cells.
  4. Supersomes, microsomal isolated from insect cells transfected with baculovirus containing CYP2B6.
  5. IC50 values.
  6. Specific time-dependent inhibitor.

Table 2. Preferred and acceptable chemical substrates for in vitro experiments* (9/25/2006)

CYPSubstrate
Preferred
Km
(µM)
Substrate
Acceptable
Km
(µM)

1A2

phenacetin-O-deethylation1.7-1527-ethoxyresorufin-O-deethylation
theophylline-N-demethylation
caffeine-3-N-demethylation
tacrine 1-hydroxylation
0.18-0.21
280-1230
220-1565
2.8, 16

2A6

coumarin-7-hydroxylation
nicotine C-oxidation
0.30-2.3
13-162
  

2B6

efavirenz hydroxylase
bupropion-hydroxylation
17-23
67-168
propofol hydroxylati on
S-mephenytoin-N-demethylation
3.7-94
1910

2C8

Taxol 6-hydroxylation5.4-19amodiaquine N-deethylation
rosiglitazone para-hydroxylation
2.4,
4.3-7.7

2C9

tolbutamide methyl-hydroxylation
S-warfarin 7-hydroxylation
diclofenac 4’-hydroxylation
67-838
1.5-4.5
3.4-52
flurbiprofen 4’-hydroxylation
phenytoin-4-hydroxylation
 
6-42
11.5-117

2C19

S-mephenytoin 4’-hydroxylation13-35omeprazole 5-hydroxylation
fluoxetine O-dealkylation
17-26
3.7-104

2D6

( ± )-bufuralol 1’-hydroxylation
dextromethorphan O-demethylation
9-15
0.44-8.5
debrisoquine 4-hydroxylation
 
5.6

2E1

chlorzoxazone 6-hydroxylation
 
 
39-157p-nitrophenol 3-hydroxylation
lauric acid 11-hydroxylation
aniline 4-hydroxylation
3.3
130
6.3-24

3A4/5**

midazolam 1-hydroxylation
 
 
testosterone 6 b -hydroxylation
 
1-14
 
 
52-94
erythromycin N-demethylation
dextromethorphan N-demethylation
triazolam 4-hydroxylation
terfenadine C-hydroxylation
nifedipine oxidation
33 – 88
133-710
234
15
5.1- 47

* Note that this is not an exhaustive list (created May 1, 2006).

** Recommend use of 2 structurally unrelated CYP3A4/5 substrates for evaluation of in vitro CYP3A inhibition. If the drug inhibits at least one CYP3A substrate in vitro, then in vivo evaluation is warranted.



Table 3. In Vitro CYP Inducers (7/28/2011)

 

CYP

 

In Vitro Inducer *
as Positive Controls

Recommended Concentration
(µM) of the Positive Controls

Reported
Fold Induction
In Enzyme Activities

1A2

omeprazole
lansoprazole

25-100
10

14-24
10

2B6

phenobarbital

500-1000

5-10

2C8

rifampin

10

2-4

2C9

rifampin

10

3.7

2C19

rifampin

10

20

2D6

none identified

 

 

3A4

rifampin

10-50

4-31

*Note that this is not an exhaustive list.  For an updated list, see the following link
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.


 In vivo

  Table 4. Examples of in vivo substrate, inhibitor, and inducer of specific CYP enzymes for evaluation (oral administration) (1) * (5/1/2006)

CYPSubstrateInhibitorInducer
1A2theophylline, caffeinefluvoxaminesmokers versus non-smokers (2)
2B6efavirenz rifampin   
2C8repaglinide, rosiglitazonegemfibrozilrifampin 
2C9warfarin, tolbutamidefluconazole, amiodarone
(use of PM versus EM subjects) (3)
rifampin
2C19omeprazole, esoprazole,
lansoprazole, pantoprazole
omeprazole, fluvoxamine, moclobemide
(use of PM versus EM subjects) (3)
rifampin
2D6desipramine, dextromethorphan, atomoxetineparoxetine, quinidine, fluoxetine
(use of PM versus EM subjects) (3)
none identified
2E1chlorzoxazonedisulfirumethanol
3A4/
3A5
 
midazolam, buspirone,
felodipine,
lovastatin, eletriptan, sildenafil, simvastatin, triazolam
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycinrifampin, carbamazepine

* Note that this is not an exhaustive list (created May 1, 2006).

  1. Substrates for any particular CYP enzyme listed in this table are those with plasma AUC values increased by 2-fold or higher when co-administered with inhibitors of that CYP enzyme; for CYP3A, only those with plasma AUC increased by 5-fold or higher are listed. Inhibitors listed are those that increase plasma AUC values of substrates for that CYP enzyme by 2-fold or higher. For CYP3A inhibitors, only those that increase AUC of CYP3A substrates by 5-fold or higher are listed. Inducers listed are those that decrease plasma AUC values of substrates for that CYP enzyme by 30% or higher.
  2. A clinical study can be conducted in smokers as compared to non-smokers (in lieu of an interaction study with an inducer), when appropriate.
  3. A clinical study can be conducted in poor metabolizers (PM) as compared to extensive metabolizers (EM) for the specific CYP enzyme (in lieu of an interaction study with an inhibitor), when appropriate.

 Classification of Inhibitors

Table 5.  Classification of In Vivo Inhibitors of CYP Enzymes(1) (7/28/2011)http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.


CYP Enzymes

Strong Inhibitors(2) 
≥ 5-fold increase in AUC
or > 80% decrease in CL

Moderate inhibitors(3) 
≥ 2 but < 5-fold increase in AUC
or 50-80% decrease in CL

Weak inhibitors(4) 
≥ 1.25 but < 2-fold increase in AUC
or 20-50% decrease in CL

CYP1A2

Ciprofloxacin, enoxacin,
fluvoxamine

Methoxsalen, mexiletine,
oral contraceptives, phenylpropanolamine,
thiabendazole, zileuton

Acyclovir, allopurinol, caffeine, cimetidine,
Daidzein,(5), disulfiram, Echinacea,(5) famotidine, norfloxacin, propafenone, propranolol, terbinafine, ticlopidine, verapamil

CYP2B6

 

 

Clopidogrel, ticlopidine
prasugrel

CYP2C8

Gemfibrozil(6)

 

Fluvoxamine, ketoconazole, trimethoprim

CYP2C9

 

Amiodarone, fluconazole,
miconazole, oxandrolone

Capecitabine, cotrimoxazole,
etravirine, fluvastatin, fluvoxamine, metronidazole, sulfinpyrazone, tigecycline,
voriconazole, zafirlukast

CYP2C19

Fluconazole,(7)
Fluvoxamine,(8)
ticlopidine(9)

Esomeprazole, fluoxetine, moclobemide,
omeprazole, voriconazole

Allicin (garlic derivative), armodafinil, carbamazepine,
cimetidine,
etravirine,
human growth hormone (rhGH),
felbamate,
ketoconazole,
oral contraceptives(10)

CYP3A

Boceprevir,
clarithromycin, conivaptan,
grapefruit juice,(11) indinavir, itraconazole, ketoconazole,
lopinavir/ritonavir,
mibefradil, (12)
nefazodone, nelfinavir,
posaconazole, ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole

Amprenavir, aprepitant,
atazanavir, ciprofloxacin,
darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice,(11)
imatinib, verapamil

Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine,
cyclosporine, fluoxetine, fluvoxamine, ginkgo,(5) goldenseal,(5)
isoniazid, nilotinib,
oral contraceptives, ranitidine, ranolazine,
tipranavir/ritonavir, zileuton

CYP2D6

Bupropion, fluoxetine,
paroxetine, quinidine

Cinacalcet, duloxetine,
terbinafine

Amiodarone, celecoxib,
cimetidine, desvenlafaxine, diltiazem, diphenhydramine, Echinacea,(5) escitalopram, febuxostat, gefitinib,
hydralazine, hydroxychloroquine,
imatinib, methadone,
oral contraceptives, propafenone, ranitidine,
ritonavir, sertraline,
telithromycin, verapamil

  1. Please note the following:  This is not an exhaustive list.  For an updated list, see the following link
  2. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP by equal or more than 5-fold.
  3. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold.
  4. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP by less than 2-fold but equal to or more than 5-fold.
  5. Herbal product.
  6. Gemfibrozil also inhibits OATP1B1.
  7. Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
  8. Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and CYP3A;
  9. Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2.
  10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
  11. The 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 as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).
  12. Withdrawn from the United States market because of safety reasons.

Table 6.  Classification of In Vivo Inducers of CYP Enzymes(1) (7/28/2011)

CYP Enzymes

Strong Inducers
≥ 80% decrease in AUC

Moderate Inducers
50-80% decrease in AUC

Weak Inducers
20-50% decrease in AUC

CYP1A2

 

Montelukast, phenytoin, smokers versus non-smokers(2)

Moricizine, omeprazole, phenobarbital,

CYP2B6

 

Efavirenz, rifampin

Nevirapine

CYP2C8

 

Rifampin

 

CYP2C9

 

Carbamazepine,
rifampin

Aprepitant, bosentan, phenobarbital, St. John’s Wort(3,4)

CYP2C19

 

Rifampin

Artemisinin

CYP3A

Avasimibe,(5) carbamazepine, phenytoin, rifampin, St. John’s wort(3)

Bosentan, efavirenz, etravirine, modafinil, nafcillin

Amprenavir, aprepitant, armodafinil, echinacea,(4) pioglitazone, prednisone, rufinamide

CYP2D6

None known

None known

None known

(1) Please note the following:  This is not an exhaustive list.  For an updated list, see the following link: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.
(2) For a drug that is a substrate of CYP1A2, the evaluation of the effect of induction of CYP1A2 can be carried out by comparative PK studies in smokers vs. non-smokers. 
(3) The effect of St. John’s wort varies widely and is preparation-dependent.
(4) Herbal product.
(5) Not a marketed drug.


 Classification of Substrates

Table 7. Examples(1) of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow Therapeutic Range (7/28/2011)

CYP Enzymes

Sensitive substrates(2)

Substrates with
narrow therapeutic range(3)

CYP1A2

Alosetron, caffeine,
duloxetine, melatonin, ramelteon,
tacrine, tizanidine

Theophylline, tizanidine

CYP2B6 (4)

Bupropion, efavirenz

 

CYP2C8

Repaglinide(5)

Paclitaxel

CYP2C9

Celecoxib

Warfarin, phenytoin

CYP2C19

Lansoprazole, omeprazole, S-mephenytoin

S-mephenytoin

CYP3A(6)

Alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, eletriptan, eplerenone, everolimus, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tolvaptan, tipranavir, triazolam, vardenafil

Alfentanil, astemizole,(7) cisapride,(7) cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus,
terfenadine(7)

CYP2D6

Atomoxetine, desipramine,
dextromethorphan, metoprolol,
nebivolol, perphenazine, tolterodine,
venlafaxine

Thioridazine

(1)  Note that this is not an exhaustive list.  For an updated list, see the following link: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.
(2) Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a known CYP inhibitor.
(3)  CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
(4) The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they represent the most sensitive substrates studied with available inhibitors evaluated to date.
(5) Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the inhibition of OATP1B1 by the investigational drug has been ruled out. 
(6) Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the observed increase in exposure could be due to inhibition of both CYP3A and P-gp.
(7) Withdrawn from the United States market because of safety reasons.
 

 


 

 P-gp Transporters

 Table 8. Acceptable In Vitro P-gp Substrates * (5/1/2006)

  Ratio**
DrugConc. Used
(µM)
Caco-2MDR1-
MDCK***
MDR1-
LLCPK***
Digoxin0.01-104-1444
Loperamide1-102-5 3.4
Quinidine0.053 5
Vinblastine a0.004-102-18> 9 b3
Talinolol3026  

* Note that this is not an exhaustive list (created May 1, 2006).

** P app, B-A / P app, A-B; P app = apparent permeability

*** Data for MDR1-MDCK and MDR1-LLCPK are the ratio observed in transfected cells relative to the ratio observed in respective wild-type cells.

a Vinblastine is also a substrate for MRP2 that is constitutively expressed in Caco-2, and wild type MDCK and LL-CPK1 cells.

b Data are derived from net B to A flux in the absence of GF120918, a potent P-gp inhibitor, relative to that observed in the presence of GF120918.


Table 9. In Vitro P-gp Inhibitors * (5/1/2006)

 
 
Inhibitor
 
IC50 (µM)
Ki (µM)
Caco-2* 
 
Caco-2* 
 

MDCK-
MDR1*

 
 

LLC-PK1
MDR1**

 
 

Cyclosporine A a1.30.52.21.3
Ketoconazole a1.2  5.3
LY3359790.024   
Nelfinavir a1.4   
Quinidine b2.23.28.6 
Ritonavir a3.8   
Saquinavir a6.5   
Tacrolimus0.74   
Valspodar (PSC833)0.11   
Verapamil2.181523
Elacridar
(GF120918)
(GG 918)
 0.40.4 
Reserpine 1.411.5 

* Note that this is not an exhaustive list (created May 1, 2006).

* Digoxin as a P-gp substrate

** Vinblastine as a P-gp substrate

a also CYP3A inhibitor

b also CYP2D6 inhibitor


 Major Human Transporters

Table 10. Major human transporters * (1) (5/1/2006)

GeneAliasesTissueSubstrateInhibitorInducer
ABCB1 P-gp, MDR1intestine, liver, kidney, brain, placenta, adrenal, testesdigoxin, fexofenadine, indinavir, vincristine, colchicine. topotecan, paclitaxelritonavir,
cyclosporine,
verapamil, erythromycin, ketocoanzole, itraconazole, quinidine, elacridar (GF120918) LY335979, valspodar (PSC 833)
rifampin, St John’s Wort
ABCB4 MDR3liverdigoxin, paclitaxel, vinblastine  
ABCB11 BSEPlivervinblastine  
ABCC1 MRP1intestine, liver, kidney, brainadefovir, indinavir  
ABCC2 MRP2, CMOATintestine, liver, kidney, brainindinavir, cisplatin,cyclosporine 
ABCC3 MRP3, CMOAT2intestine, liver, kidney, placenta, adrenaletoposide, methotrexate, tenoposide  
ABCC4 MRP4    
ABCC5 MRP5    
ABCC6 MRP6liver, kidneycisplatin, daunorubicin  
ABCG2 BCRPintestine, liver, breast, placentadaunorubicin, doxorubicin,
topotecan, rosuvastatin, sulfasalazine
elacridar (GF120918) 
SLCO1B1 OATP1B1, OATP-C
OATP2
liverrifampin, rosuvastatin, methotrexate, pravastatin, thyroxinecyclosporine
rifampin
 
SLCO1B3 OATP1B3, OATP8,liverdigoxin, methotrexate, rifampin,  
SLCO2B1 SLC21A9, OATP-Bintestine, liver, kidney, brainpravastatin  
SLC10A1 NTCPliver, pancreasrosuvastatin  
SLC10A2 ASBTileum, kidney, biliary tract   
SLC15A1 PEPT1intestine, kidneyampicillin, amoxicillin, captopril, valacyclovir  
SLC15A2 PEPT2kidneyampicillin, amoxicillin, captopril, valacyclovir  
SLC22A1 OCT-1liveracyclovir, amantadine, desipramine, ganciclovir
metformin
disopyramide, midazolam, phenformin, phenoxy-benzamine quinidine,
quinine, ritonavir, verapamil
 
SLC22A2 OCT2kidney, brainamantadine,
cimetidine, memantine
desipramine, phenoxy-benzamine quinine 
SLC22A3 OCT3skeletal muscle, liver, placenta, kidney, heartcimetidinedesipramine, prazosin, phenoxy-benzamine 
SLC22A4 OCTN1kidney, skeletal muscle, placenta, prostate, heartquinidine, verapamil  
SLC22A5 OCTN2kidney, skeletal muscle, prostate, lung, pancreas, heart, small intestine, liverquinidien, verapamil  
SLC22A6 OAT1kidney, brainacyclovir, adefovir,
methotrexate, zidovudine
probenecid, cefadroxil, cefamandole, cefazolin, 
SLC22A7 OAT2liver, kidneyzidovudine  
SLC22A8 OAT3kidney, braincimetidine, methotrexate, zidovudineprobenecid, cefadroxil, cefamandole, cefazolin, 

* Note that this is not an exhaustive list (created May 1, 2006).

  1. ABC:ATP-binding cassette transporter superfamily; SLC: solute-linked carrier transporter family; SLCO: solute-linked carrier organic anion transporter family; MDR1: multi-drug resistance; MRP: multi-drug resistance related protein; BSEP:bile salt export pump; BCRP: breast cancer resistance protein; OAT: organic anion transporter; OCT: organic cation transporter; NTCP: sodium taurocholate co-transporting polypeptide; ASBT: apical sodium-dependent bile salt transporter.

 

Table 11.  Selected Transportera-Mediated Clinical Significant Drug-Drug Interactions (7/28/2011)

Gene

Aliasesa

Tissue

Function

Interacting Drug

Substrate
(Affected Drug)

Changes in Substrate Plasma AUC
(AUC ratios)

ABC Transporters of clinical importance in the absorption, disposition, and excretion of drugs

ABCB1

P-gp,
MDR1

Intestinal enterocyte, kidney proximal tubule, hepatocyte (canalicular), brain endothelia

Efflux

Dronedarone

Digoxin

2.6-fold

Quinidine

Digoxin

1.7-fold

Ranolazine

Digoxin

1.6-fold

Tipranavir/Ritonavir

Loperamide

0.5-fold

Tipranavir/Ritonavir

Saquinavir/Ritonavir

0.2-fold

ABCG2

BCRP

Intestinal enterocyte, hepatocyte (canalicular), kidney proximal tubule, brain endothelia, placenta, stem cells, mammary gland (lactating)

Efflux

GF120918

Topotecan

2.4-fold

SLC Transporters of clinical importance in the disposition and excretion of drugs

SLCO1B1

OATP1B1
OATP-C
OATP2
LST-1

Hepatocyte (sinusoidal)

Uptake

Lopinavir/ritonavir

Bosentan

5-48 foldc

Cyclosporine

Pravastatin

9.9-fold

Rifampin (single dose)

Glyburide

2.3-fold

SLCO1B3

OATP1B3, OATP-8

Hepatocyte (sinusoidal)

Uptake

Cyclosporine

Rosuvastatin

7.1- foldd,e

Cyclosporine

Pitavastatin

4.6-foldd

Lopinavir/ritonavir

Rosuvastatin

2.1-foldd

SLC22A2

OCT2

Kidney proximal tubule

Uptake

Cimetidine

Dofetilide

1.5-fold

Cimetidine

Pindolol

1.5-fold

Cimetidine

Metformin

1.4-foldf

SLC22A6

OAT1

Kidney proximal tubule, placenta

Uptake

Probenecid

Cephradine

3.6-fold

Probenecid

Cidofovir

1.5-fold

Probenecid

Acyclovir

1.4-fold

SLC22A8

OAT3

Kidney proximal tubule, choroid plexus, brain endothelia

Uptake

Probenecid

Furosemide

2.9-foldg

 

a Abbreviations:  BCRP, breast cancer resistance protein; P-gp, p-glycoprotein; MDR, multidrug resistance:  LST, liver-specific transporters; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; OAT, organic anion transporter
b Implicated transporter refers to the likely transporter; however, because the studies are in vivo, it is not possible to assign definitively specific transporters to these interactions. 
c Minimum predose plasma level (Ctrough) data from Day 4 (48-fold), Day 10 (5-fold) after co-administration.
d Interaction could be partly mediated by OATP1B1.
e Interaction could be partly mediated by BCRP.
f Interaction could be partly mediated by MATE-1/MATE-2K.
g Interaction could be partly mediated by OAT1.


Table 12. Examples of In Vivo Inhibitors and Inducers of Selected Transporters(1) (7/28/2011)

Transporter

Gene

Inhibitor(2)

Inducer(3)

P-gp

ABCB1

Amiodarone, azithromycin,(4) captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin,(5) felodipine,  itraconazole, ketoconazole,(4) lopinavir and ritonavir, quercetin,(4) quinidine, ranolazine, verapamil

Avasimibe, (6) carbamazepine,(7) phenytoin, rifampin, St John’s wort,(8) tipranavir/ritonavir

BCRP

ABCG2

Cyclosporine, elacridar (GF120918), eltrombopag, gefitinib

Not known

OATP1B1

SLCO1B1

Atazanavir,(10) cyclosporine, eltrombopag, gemfibrozil, lopinavir, (10)  rifampin,(9)  ritonavir, (11) saquinavir, (10)  tipranavir(10)

Not known

OATP1B3

SLCO1B3

Atazanavir, (10)  cyclosporine, lopinavir, (10)  rifampin, (9)  ritonavir,(11)  saquinavir(10)

Not known

 

 

 

 

OCT2

SLC22A2

Cimetidine, quinidine

Not known

OAT1

SLC22A6

Probenecid

Not known

OAT3

SLC22A8

Probenecid cimetidine, diclofenac

Not known

  • Please note this is not an exhaustive list.  For an updated list, see the following link http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.
  • Inhibitors listed for P-gp are those that showed >25% increase in digoxin AUC or otherwise indicated if substrate is other than digoxin.
  • Inducers listed for P-gp are those that showed >20% decrease in digoxin AUC or otherwise indicated if substrate is other than digoxin.
  • Inhibitors listed are those that showed >25% increase in fexofenadine AUC.
  • Inhibitors listed are those that showed >25% increase in talinolol AUC.
  • Not a marketed drug.
  • Inducers listed are those that showed >20% decrease in fexofenadine AUC.
  • Herbal product.
  • Given as a single dose.
  • In vitro inhibitors for OATP.  Separation of the in vivo inhibition effect from ritonavir is difficult because this drug is usually co-administered with ritonavir.
  • The in vivo inhibition effect of ritonavir cannot be easily estimated because it is usually co-administered with other HIV protease inhibitors that are inhibitors for OATP as well.


Table 13.  Examples of In Vivo Substrates for Selected Transporters(1) (7/28/2011)

Transporter

Gene

Substrate

P-gp

ABCB1

Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan

BCRP

ABCG2

Methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan

OATP1B1

SLCO1B1

Atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, valsartan, olmesartan

OATP1B3

SLCO1B3

Atorvastatin, rosuvastatin, pitavastatin, telmisartan,(2) valsartan, olmesartan

OCT2

SLC22A2

Amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin

OAT1

SLC22A6

Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zalcitabine, zidovudine

OAT3

SLC22A8

Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, zidovudine, oseltamivir acid, (the active metabolite of oseltamivir), penicillin G, pravastatin, rosuvastatin, sitagliptin

 (2)  Selective for OATP1B3.


Table 14. Examples of In Vivo CYP3A and P-gp Inhibitors and Their Relative Potency (7/28/2011)

 

P-gp Inhibitor

Non-P-gp Inhibitor

Strong CYP3A Inhibitor

Itraconazole, lopinavir/ritonavir,
clarithromycin,
ritonavir,*
ketoconazole,*
indinavir/ritonavir,*
conivaptan

Voriconazole, nefazodone

Moderate CYP3A Inhibitor

Verapamil, erythromycin,* diltiazem, dronedarone

None identified

Weak CYP3A Inhibitor

Quinidine, ranolazine, amiodarone, felodipine,
azithromycin*

Cimetidine

            *  Data derived with fexofenadine; all other data were derived with digoxin.

Notes:
(1) The University of Washington Drug Interaction Database was used to search the data that defined the in vivo potency of various inhibitors for CYP3A (midazolam was searched as a substrate) and P-gp (digoxin or fexofenadine was searched as a substrate).
(3) Strong, moderate, or weak CYP3A inhibitors are defined as those drugs that increase the AUC of oral midazolam or other CYP3A substrates ≥5-fold, 2-5-fold, and 1.25-2-fold, respectively.