Drugs

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


Table 1-1: Examples of in vitro marker reactions for P450-mediated metabolism (9/26/2016)

EnzymeMarker reaction
CYP1A2Phenacetin O-deethylation, 7-Ethoxyresorufin-O-deethylation
CYP2B6Efavirenz hydroxylation, Bupropion hydroxylation
CYP2C8Paclitaxel 6α-hydroxylation, Amodiaquine N-deethylation
CYP2C9S-Warfarin 7-hydroxylation, Diclofenac 4'-hydroxylation
CYP2C19S-Mephenytoin 4'-hydroxylation
CYP2D6Bufuralol 1'-hydroxylation, Dextromethorphan O-demethylation
CYP3A4/5*Midazolam 1'-hydroxylation, Testosterone 6β-hydroxylation

* Recommend the use of 2 structurally unrelated CYP3A4/5 substrates for evaluation of in vitro CYP3A4/5 inhibition.


Table 1-2: Examples of in vitro selective inhibitors for P450-mediated metabolism (9/26/2016)

EnzymeInhibitor
CYP1A2α-Naphthoflavone, Furafylline*
CYP2B6**Sertraline, Phencyclidine*, Thiotepa*, Ticlopidine*
CYP2C8Montelukast, Quercetin, Phenelzine*
CYP2C9Sulfaphenazole, Tienilic acid*
CYP2C19**S-(+)-N-3-benzyl-nirvanol, Nootkatone, Ticlopidine*
CYP2D6Quinidine, Paroxetine*
CYP3A4/5Itraconazole, Ketoconazole, Azamulin*, Troleandomycin*, Verapamil*

Most chemical inhibitors are not specific for an individual CYP enzyme. The selectivity and potency of inhibitors should be verified in the same experimental conditions using probe substrates for each CYP enzyme.

* Time-dependent inhibitors. **No selective inhibitor is available in vitro for CYP2C19- and CYP2B6-mediated metabolisms. The inhibitors listed here can be used together with other information, such as metabolic profiles obtained from single enzyme expression systems.


Table 1-3. Examples of in vitro inducers for P450-mediated metabolism (9/26/2016)

EnzymeInducer*
CYP1A2Omeprazole, Lansoprazole
CYP2B6Phenobarbital
CYP2C8Rifampicin
CYP2C9Rifampicin
CYP2C19Rifampicin
CYP3A4/5Rifampicin

Table 2-1: Examples of clinical index substrates for P450-mediated metabolism (for use in index clinical DDI studies) (9/26/2016)

 Sensitive index substrates unless otherwise noted
CYP1A2caffeine, tizanidine
CYP2B6(a)-
CYP2C8repaglinide(b)
CYP2C9tolbutamide(c), S-warfarin(c)
CYP2C19lansoprazole (c,d), omeprazole
CYP2D6desipramine, dextromethorphan, nebivolol
CYP3Amidazolam, triazolam

* Note: Index substrates predictably exhibit exposure increase due to inhibition or induction of a given metabolic pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main clinical DDI guidance document for details. Sensitive index substrates are index drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drug that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.

This table is prepared to provide examples of clinical sensitive or moderate sensitive index substrates and is not intended to be an exhaustive list. Index substrates listed in this table were selected considering their sensitivity, specificity, safety profiles, and adequate number of reported clinical DDI studies with different in vivo inhibitors (≥ 3 for CYP3A or ≥ 2 for CYP1A2, 2C8, 2C9, 2C19, and 2D6). DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61], and the list of references is available here.

(a) We currently do not have sensitive index substrates for CYP2B6.
(b) Also OATP1B1 substrate.
(c) Moderate sensitive substrates.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1.


Table 2-2: Examples of clinical index inhibitors for P450-mediated metabolisms (for use in index clinical DDI studies) (9/26/2016)

 Strong index inhibitorsModerate index inhibitors
CYP1A2fluvoxamine(a)-
CYP2B6(b)--
CYP2C8clopidogrel(c), gemfibrozil(d)-
CYP2C9-fluconazole(e)
CYP2C19fluvoxamine(a)-
CYP2D6fluoxetine(f), paroxetinemirabegron
CYP3Aclarithromycin(g), itraconazole(g)erythromycin, fluconazole(e), verapamil(g)

Note: Index inhibitors predictably inhibit metabolism via a given pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main guidance documents for details. Strong and moderate inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold and ≥2 to <5-fold, respectively.

This table is prepared to provide examples of clinical index inhibitors and is not intended to be an exhaustive list. Index inhibitors listed in this table were selected based on potency and selectivity of inhibition, safety profiles, and adequate number of reported clinical DDI studies with different in vivo substrates [≥ 3 for CYP3A, ≥ 2 for CYP1A2, 2C9, 2C19, and 2D6, or ≥ 1 for CYP2C8 (strong inhibitors)]. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61)], and the list of references is available here.

(a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A.
(b) We currently do not have index inhibitors for CYP2B6.
(c) Strong inhibitor of CYP2C8, weak inhibitor of CYP2B6, and inhibitor of OATP1B1. The glucoronide metabolite is also an inhibitor for CYP2C8 and OATP1B1.
(d) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3. The glucoronide metabolite is also an inhibitor for CYP2C8 and OATP1B1.
(e) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.
(f) Strong inhibitors of CYP2C19 and CYP2D6. (g) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; OATP1B1: organic anion transporting polypeptide 1B1; OAT3: organic anion transporter 3; P-gp: P-glycoprotein.


Table 2-3: Examples of clinical index inducers for P450-mediated metabolisms (for use in index clinical DDI studies) (9/26/2016)

 Strong inducersModerate inducers
CYP1A2--
CYP2B6-rifampin(a)
CYP2C8-rifampin(a)
CYP2C9-rifampin(a)
CYP2C19rifampin(a)-
CYP3Aphenytoin(b), rifampin(a)-

Note: Index inducers predictably induce metabolism via a given pathway and are commonly used in prospective clinical DDI studies. See section IV.A.2. of the main guidance documents for details. Strong and moderate index inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80% and ≥50% to <80%, respectively.

This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. Index inducers listed in this table were selected based on potency of induction, safety profiles, and number of reported clinical DDI studies with different in vivo substrates (≥ 2 substrates). DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61], and the list of references is available here.

(a) Strong inducer of CYP1A2, CYP2C19, CYP3A, and moderate inducer of CYP2B6, CYP2C8, CYP2C9.
(b) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.


Table 3-1: Examples of clinical substrates for P450-mediated metabolism (for concomitant use clinical DDI studies and/or drug labeling) (9/26/2016)

 Sensitive substratesModerate sensitive substrates
CYP1A2alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidineclozapine, pirfenidone, ramosetron
CYP2B6bupropion(a)efavirenz(a)
CYP2C8repaglinide(b)montelukast, pioglitazone, rosiglitazone
CYP2C9celecoxib(c)glimepiride, phenytoin, tolbutamide, warfarin
CYP2C19S-mephenytoin, omeprazolediazepam, lansoprazole(d), rabeprazole, voriconazole
CYP2D6atomoxetine, desipramine, dextromethorphan , eliglustat(e), nebivolol, nortriptyline, perphenazine, tolterodine, venlafaxineamitriptyline, encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, trimipramine,
CYP3Aalfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir(f), ebastine, everolimus, ibrutinib, lomitapide, lovastatin(g), midazolam, naloxegol, nisoldipine, saquinavir(f), simvastatin(g), sirolimus, tacrolimus, tipranavir(f), triazolam, vardenafilalprazolam, aprepitant, atorvastatin(c), colchicine, eliglustat(e), pimozide, rilpivirine, rivaroxaban, tadalafil
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir(f), lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 

Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line. Other elimination pathways may also contribute to the elimination of the substrates listed in the table above and should be considered when assessing the drug interaction potential.

This table is prepared to provide examples of clinical substrates and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].

(a) Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of other pathway(s).
(b) OATP1B1 substrate.
(c)Listed based on pharmacogenetic studies.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.
(e) Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A.
(f) Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.
(g) Acid form is an OATP1B1 substrate

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1.


Table 3-2: Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (9/26/2016)

 Strong inhibitorsModerate inhibitorsWeak inhibitors
CYP1A2ciprofloxacin, enoxacin, fluvoxamine(a), zafirlukastmethoxsalen, mexiletine ,oral contraceptivesacyclovir, allopurinol, cimetidine, peginterferon alpha-2a, piperine, zileuton
CYP2B6--clopidogrel(b), tenofovir, ticlopidine(c), voriconazole(d)
CYP2C8clopidogrel(b), gemfibrozil(e)deferasirox, teriflunomidetelithromycin, trimethoprim
CYP2C9-amiodarone, felbamate, fluconazole(f), miconazole, piperinediosmin, disulfiram, fluvastatin, fluvoxamine(a), voriconazole
CYP2C19fluconazole(f), fluoxetine(g), fluvoxamine(a), ticlopidine-omeprazole, voriconazole
CYP2D6bupropion, fluoxetine(g), paroxetine, quinidine(h), terbinafinecimetidine, cinacalcet, duloxetine, fluvoxamine(a), mirabegronabiraterone, amiodarone, celecoxib, cimetidine, clobazam, cobicistat, desvenlafaxine, escitalopram, labetalol, lorcaserin, ritonavir(h,i,j), sertraline, vemurafenib
CYP3Aboceprevir, cobicistat(h), conivaptan(h), danoprevir and ritonavir(j), elvitegravir and ritonavir(j), grapefruit juice(k), indinavir and ritonavir(j), itraconazole(h), ketoconazole, lopinavir and ritonavir(h,j), paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)(j), posaconazole, ritonavir(h,j), saquinavir and ritonavir(h,j), telaprevir(h), tipranavir and ritonavir(h,j), troleandomycin, voriconazoleaprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone(h), erythromycin, fluconazole(f), fluvoxamine(a), imatinib, tofisopam, verapamil(h)chlorzoxazone, cilostazol, fosaprepitant, istradefylline, ivacaftor(h), lomitapide, ranitidine, ranolazine(h), tacrolimus, ticagrelor(h)
clarithromycin(h), diltiazem(h), idelalisib, nefazodone, nelfinavir(h)  

Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively. Strong inhibitors of CYP3A causing ≥10-fold increase in AUC of sensitive index substrate(s) are shown above the dashed line.

This table is prepared to provide examples of clinical inhibitors and is not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].

(a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A.
Strong inhibitor of CYP2C8, weak inhibitor of CYP2B6, and inhibitor of OATP1B1.
(c) Strong inhibitor of CYP2C19 and weak inhibitor of CYP2B6.
(d) Strong inhibitor of CYP2C19 and CYP3A, and weak inhibitor of CYP2B6.
(e) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3.
(f) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. (g) Strong inhibitors of CYP2C19 and CYP2D6.
(h) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).
(i) Strong inhibitors of CYP3A and weak inhibitor of CYP2D6.
(j) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of combination regimens on CYP3A activities.
(k) 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).

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; HIV: human immunodeficiency virus; HCV: hepatitis C virus; OATP1B1: organic anion transporting polypeptide 1B1; OAT3: organic anion transporter 3; P-gp: P-glycoprotein.


Table 3-3: Examples of clinical inducers for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (9/26/2016)

 Strong inducersModerate inducersWeak inducers
CYP1A2 phenytoin(a) rifampin(b), ritonavir(c), smoking, teriflunomide-
CYP2B6carbamazepine(d)efavirenz(e), rifampin(a), ritonavir(c)nevirapine
CYP2C8-rifampin(a)-
CYP2C9-aprepitant, carbamazepine(d), enzalutamide(f), rifampin(a), ritonavir(c)-
CYP2C19rifampin(a), ritonavir(c)efavirenz(e), enzalutamide(f), phenytoin(b)-
CYP3Acarbamazepine(d), enzalutamide(f), mitotane, phenytoin(b), rifampin(a), St. John’s wort(g)bosentan, efavirenz, etravirine, modafinilarmodafinil, rufinamide

Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.

This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].

(a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
(b) Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9.
(c) Strong inducer of CYP2C19 and moderate inducer of CYP1A2, CYP2B6, CYP2C9.
(d) Strong inducer of CYP2B6, CYP3A, and moderate inducer of CYP2C9.
(e) Moderate inducer of CYP2B6, CYP2C19 and weak inducer of CYP3A.
(f) Strong inducer of CYP3A and moderate inducer of CYP2C9, CYP2C19, CYP3A.
(g) The effect of St. John’s wort varies widely and is preparation-dependent.

Abbreviations:
AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction.


Table 4-1: Examples of in vitro substrates for transporters (9/26/2016)

TransporterGeneSubstrate
P-gpABCB1Digoxin(a)
Fexofenadine(b,c,d)
Loperamide
Quinidine
Talinolol(c)
Vinblastine(c)
BCRPABCG22-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)(c,e)
Coumestrol
Daidzein
Dantrolene
Estrone-3-sulfate(b,f)
Genistein
Prazosin(e)
Sulfasalazine
OATP1B1,
OATP1B3
SLCO1B1,
SLCO1B3
Cholecystokinin octapeptide(CCK-8) (g)
Estradiol-17β-glucuronide(h)
Estrone-3-sulfate(i)
Pitavastatin(c,e,f,j)
Pravastatin(c,f,k)
Telmisartan(l)
Rosuvastatin(c,f,j,k)
OAT1SLC22A6Adefovir
p-aminohippurate
Cidofovir
Tenofovir
OAT3SLC22A8Benzylpenicillin(b)
Estrone-3-sulfate (j,m)
Methotrexate (b,c,j,n)
Pravastatin(b,c)
MATE1, MATE-2KSLC47A1, SLC47A2Metformin(o)
1-methyl-4-phenylpyridinium (MPP+)(o)
Tetraethylammonium (TEA)(o)
OCT2SLC22A2Metformin (o)
1-methyl-4-phenylpyridinium (MPP+)(o)
Tetraethylammonium (TEA)(o)

Note:
(a) Also a substrate of OATP1B3.
(b) Also a substrate of OATPs.
(c) Also a substrate of MRP2.
(d) Also a substrate of MRP3.
(e) Also a substrate of P-gp.
(f) Also a substrate of NTCP.
(g) Selective substrate of OATP1B3 (vs. OATP1B1).
(h) The Ki value is estimated to be lower in inhibition studies. This substance has appropriate characteristics of a marker drug.
(i) Selective substrate of OATP1B1 (vs. OATP1B3). It is reported that the estimated Ki value in inhibition studies tends to be lower.
(j) Also a substrate of BCRP.
(k) Also a substrate of OAT3.
(l) Selective substrate of OATP1B3 (vs. OATP1B1). Addition of albumin to the study system should be considered to decrease the effects of nonspecific absorption.
(m) Also a substrate of OATP1B1.
(n) Also a substrate of OAT1.
(o) Substrate of OCTs and MATEs.

This table is prepared to provide examples of in vitro substrates for various transporters and not intended to be an exhaustive list.


Table 4-2: Examples of in vitro inhibitors for transporters (9/26/2016)

TransporterGeneInhibitor
P-gpABCB1Cyclosporine(a)
Elacridar (GF120918)(b)
Ketoconazole(c)
Quinidine(d)
Reserpine(e)
Ritonavir(f)
Tacrolimus(f)
Valspodar (PSC833)(e)
Verapamil(d)
Zosuquidar (LY335979)
BCRPABCG2Elacridar (GF120918)(g)
Fumitremorgin C
Ko134
Ko143
Novobiocin
Sulfasalazine
OATP1B1,
OATP1B3
SLCO1B1,
SLCO1B3
Cyclosporine(c,e,g,h)
Estradiol-17β-glucuronide(b,e)
Estrone-3-sulfate (b,c)
Rifampicin
Rifamycin SV
OAT1, OAT3SLC22A6, SLC22A8Benzylpenicillin
Probenecid(f)
MATE1, MATE-2KSLC47A1, SLC47A2Cimetidine(d,i)
Pyrimethamine
OCT2SLC22A2Cimetidine(h)

Note:
(a)Inhibitor of MRP2, BCRP, NTCP and OATPs.
(b) Also an inhibitor of BCRP.
(c) Also an inhibitor of NTCP.
(d) Also an inhibitor of OCTs.
(e) Also an inhibitor of MRP2.
(f) Also an inhibitor of OATPs.
(g) Also an inhibitor of P-gp.
(h) Preincubation with inhibitors prior to inhibition studies causes a decrease of the Ki value.
(i) Also an inhibitor of OAT3.

This table is prepared to provide examples of in vitro inhibitors for various transporters and not intended to be an exhaustive list.


Table 5-1: Examples of clinical substrates for transporters (for use in clinical DDI studies and/or drug labeling) (9/26/2016)

TransporterGeneSubstrate
P-gpABCB1dabigatran, digoxin, fexofenadine(e)
BCRPABCG2rosuvastatin, sulfasalazine
OATP1B1
OATP1B3
SLCO1B1,
SLCO1B3
asunaprevir, atorvastatin, bosentan, cerivastatin, danoprevir, docetaxel(a), fexofenadine(e), glyburide, nateglinide, paclitaxel, pitavastatin(b), pravastatin, repaglinide, rosuvastatin(b), simvastatin acid
OAT1
OAT3
SLC22A6,
SLC22A8
adefovir(c), cefaclor, ceftizoxime, famotidine(d), furosemide, ganciclovir(c), methotrexate, oseltamivir carboxylate(d), penicillin G(d)
MATE1,
MATE-2K, OCT2
SLC47A1, SLC47A2, SLC22A2dofetilide, metformin

Note:
Criteria for selecting clinical substrates are as follows:

  • P-gp: (1) AUC fold-increase≥2 with verapamil or quinidine co-administration and (2) in vitro transport by P-gp expression systems, but not extensively metabolized.
  • BCRP: (1) AUC fold-increase≥2 with pharmacogenetic alteration of ABCG2 (421C>A) and (2) in vitro transport by BCRP expression systems.
  • OATP1B1/OATP1B3: (1) AUC fold-increase≥2 with rifampin (single dose) or cyclosporine A co-administration, or pharmacogenetic alteration of SLCO1B1 (521T>C) and (2) in vitro transport by OATP1B1 or OATP1B3 expression systems.
  • OAT1/OAT3: (1) AUC fold-increase≥1.5 with probenecid co-administration, (2) fraction excreted unchanged into urine as an unchanged drug ≥ 0.5, and (3) in vitro transport by OAT1 or OAT3 expression systems.
  • OCT2/MATE: Well-established substrate of cationic transport system (metformin) and a narrow therapeutic-index drug (dofetilide).

This table is prepared to provide examples of clinical substrates for various transporters and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].

(a)In vitro data suggested higher contribution of OATP1B3 than OATP1B1.
(b)In vitro and pharmacogenetic data suggested higher contribution of OATP1B1 than OATP1B3.
(c)In vitro data suggested higher contribution of OAT1 than OAT3.
(d)in vitro data suggested higher contribution of OAT3 than OAT1.
(e) Fexofenadine is a substrate for both P-gp and OATP1B.

Abbreviations:
AUC: area under the plasma concentration-time curve.


Table 5-2: Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug labeling) (9/26/2016)

TransporterGeneInhibitor
P-gp(a)ABCB1amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil
BCRPABCG2curcumin, cyclosporine A, eltrombopag
OATP1B1, OATP1B3SLCO1B1, SLCO1B3atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin (single dose), simeprevir
OAT1, OAT3SLC22A6, SLC22A8p-aminohippuric acid (PAH)(b), probenecid, teriflunomide
MATE1, MATE2-KSLC47A1, SLC47A2cimetidine, dolutegravir, isavuconazole, ranolazine, trimethoprim, vandetanib

Note:
Criteria for selecting in vivo inhibitors are as follows:

  • P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor.
  • BCRP: (1) AUC fold-increase of sulfasalazine ≥1.5 with co-administration and (2) in vitro inhibitor. Cyclosporine A and eltrombopag were also included, although the available DDI information was with rosuvastatin, where inhibition of both BCRP and OATPs may have contributed to the observed interaction.
  • OATP1B1/OATP1B3: (1) AUC fold-increase ≥2 for at least one of clinical substrates in Table 2-3 with co-administration and (2) in vitro inhibitor.
  • OAT1/OAT3: (1) AUC fold-increase ≥1.5 for at least one of clinical substrates in Table 2-3 with co-administration and (2) in vitro inhibitor.<./li>
  • OCT2/MATE: (1) AUC fold-increase of metformin ≥ 1.5 with co-administration and (2) in vitro inhibitor.

This table is prepared to provide examples of clinical inhibitors for various transporters and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].

(a)Most of P-gp inhibitors also inhibit CYP3A. (b)In vivo data suggested specific inhibition of OAT1.

Abbreviations:
AUC: area under the plasma concentration-time curve.

References

Ministry of Health, Labour and Welfare (MHLW), Japan (2014). Drug interaction guideline for drug development and labeling recommendations (Draft, in Japanese)

European Medicines Agency (2013). Guideline on the Investigation of Drug Interactions.

Page Last Updated: 09/27/2016
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English