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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)

Enzyme Marker reaction
CYP1A2 Phenacetin O-deethylation, 7-Ethoxyresorufin-O-deethylation
CYP2B6 Efavirenz hydroxylation, Bupropion hydroxylation
CYP2C8 Paclitaxel 6α-hydroxylation, Amodiaquine N-deethylation
CYP2C9 S-Warfarin 7-hydroxylation, Diclofenac 4'-hydroxylation
CYP2C19 S-Mephenytoin 4'-hydroxylation
CYP2D6 Bufuralol 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)

Enzyme Inhibitor
CYP1A2 α-Naphthoflavone, Furafylline*
CYP2B6** Sertraline, Phencyclidine*, Thiotepa*, Ticlopidine*
CYP2C8 Montelukast, Quercetin, Phenelzine*
CYP2C9 Sulfaphenazole, Tienilic acid*
CYP2C19** S-(+)-N-3-benzyl-nirvanol, Nootkatone, Ticlopidine*
CYP2D6 Quinidine, Paroxetine*
CYP3A4/5 Itraconazole, 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)

Enzyme Inducer*
CYP1A2 Omeprazole, Lansoprazole
CYP2B6 Phenobarbital
CYP2C8 Rifampicin
CYP2C9 Rifampicin
CYP2C19 Rifampicin
CYP3A4/5 Rifampicin

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
CYP1A2 caffeine, tizanidine
CYP2B6(a) -
CYP2C8 repaglinide(b)
CYP2C9 tolbutamide(c), S-warfarin(c)
CYP2C19 lansoprazole (c,d), omeprazole
CYP2D6 desipramine, dextromethorphan, nebivolol
CYP3A midazolam, 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 inhibitors Moderate index inhibitors
CYP1A2 fluvoxamine(a) -
CYP2B6(b) - -
CYP2C8 clopidogrel(c), gemfibrozil(d) -
CYP2C9 - fluconazole(e)
CYP2C19 fluvoxamine(a) -
CYP2D6 fluoxetine(f), paroxetine mirabegron
CYP3A clarithromycin(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 inducers Moderate inducers
CYP1A2 - -
CYP2B6 - rifampin(a)
CYP2C8 - rifampin(a)
CYP2C9 - rifampin(a)
CYP2C19 rifampin(a) -
CYP3A phenytoin(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) (12/03/2019)

  Sensitive substrates Moderate sensitive substrates
CYP1A2 alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine clozapine, pirfenidone, ramosetron, theophylline
CYP2B6 bupropion(a) efavirenz(a)
CYP2C8 repaglinide(b) montelukast, pioglitazone, rosiglitazone
CYP2C9 celecoxib(c) glimepiride, phenytoin, tolbutamide, warfarin
CYP2C19 S-mephenytoin, omeprazole diazepam, lansoprazole(d), rabeprazole, voriconazole
CYP2D6 atomoxetine, desipramine, dextromethorphan , eliglustat(e), nebivolol, nortriptyline, perphenazine, tolterodine, R-venlafaxine encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, trimipramine, S-venlafaxine
CYP3A alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir(f), ebastine, everolimus, ibrutinib, lomitapide, lovastatin(g), midazolam, naloxegol, nisoldipine, saquinavir(f), simvastatin(g), sirolimus, tacrolimus, tipranavir(f), triazolam, vardenafil alprazolam, 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) (03/06/2020)

  Strong inhibitors Moderate inhibitors Weak inhibitors
CYP1A2 ciprofloxacin, enoxacin, fluvoxamine(a) methoxsalen, mexiletine ,oral contraceptives acyclovir, allopurinol, cimetidine, peginterferon alpha-2a, piperine, zileuton
CYP2B6 - - clopidogrel(b), tenofovir, ticlopidine(c), voriconazole(d)
CYP2C8 gemfibrozil(e) clopidogrel(b), deferasirox, teriflunomide trimethoprim
CYP2C9 - amiodarone, fluconazole(f), miconazole, piperine diosmin, disulfiram, fluvastatin, fluvoxamine(a), voriconazole
CYP2C19 fluconazole(f), fluoxetine(g), fluvoxamine(a), ticlopidine felbamate omeprazole, voriconazole
CYP2D6 bupropion, fluoxetine(g), paroxetine, quinidine(h), terbinafine abiraterone, cinacalcet, duloxetine, lorcaserin, mirabegron amiodarone, celecoxib, cimetidine, clobazam, cobicistat, escitalopram, fluvoxamine(a), labetalol, ritonavir(h,i,j), sertraline, vemurafenib
CYP3A4 boceprevir, cobicistat(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), telithromycin, troleandomycin, voriconazole aprepitant, ciprofloxacin, conivaptan(l), crizotinib, cyclosporine, diltiazem(m), dronedarone(h), erythromycin, fluconazole(f), fluvoxamine(a), imatinib, tofisopam, verapamil(h) chlorzoxazone, cilostazol, cimetidine, clotrimazole, fosaprepitant, istradefylline, ivacaftor(h), lomitapide, ranitidine, ranolazine(h), ticagrelor(h)
clarithromycin(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.  Moderate inhibitor of CYP3A and Weak inhibitor of CYP2D6.
(b) Moderate inhibitor of CYP2C8 and weak inhibitor of CYP2B6.
(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).
(l) The classification is based on studies conducted with intravenously administered conivaptan.
(m) Diltiazem increased AUC of certain sensitive CYP3A substrates (e.g., buspirone) more than 5-fold.

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) (12/03/2019)

  Strong inducers Moderate inducers Weak inducers
CYP1A2   phenytoin(a) rifampin(b), ritonavir(c,d), smoking, teriflunomide -
CYP2B6 carbamazepine(e) efavirenz(e), rifampin(a) nevirapine, ritonavir(c, d)
CYP2C8 - rifampin(a) -
CYP2C9 - enzalutamide(g), rifampin(a) apalutamide, aprepitant, carbamazepine(e), ritonavir(c, d)
CYP2C19 rifampin(a) apalutamide, efavirenz(e,f), enzalutamide(g), phenytoin(b) ritonavir(c, d)
CYP3A apalutamide, carbamazepine(e), enzalutamide(g), mitotane, phenytoin(b), rifampin(a), St. John’s wort(h) bosentan, efavirenz(f), etravirine, phenobarbital, primidone armodafinil, modafinil(i), 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) Moderate inducer of CYP1A2 with dose of 800 mg/day ritonavir (not with other anti-HIV drugs). Effect on CYP1A2 at lower doses of ritonavir is unknown.
(d) Weak inducer of CYP2B6, CYP2C9, and CYP2C19. Classification is based on studies conducted with ritonavir itself (not with other anti-HIV drugs) at doses of 100-200 mg/day, although larger effects have been reported in literature for high doses of ritonavir.
(e) Strong inducer of CYP2B6, CYP3A, and weak inducer of CYP2C9.
(f) Moderate inducer of CYP2B6, CYP2C19 and CYP3A.
(g) Strong inducer of CYP3A and moderate inducer of CYP2C9, and CYP2C19.
(h) The effect of St. John’s wort varies widely and is preparation-dependent.
(i) Based on effect of 200 mg/day modafinil. A higher dose (400 mg/day) modafinil had larger induction effect on CYP3A.

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)

Transporter Gene Substrate
P-gp ABCB1 Digoxin(a)
Fexofenadine(b,c,d)
Loperamide
Quinidine
Talinolol(c)
Vinblastine(c)
BCRP ABCG2 2-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)
OAT1 SLC22A6 Adefovir
p-aminohippurate
Cidofovir
Tenofovir
OAT3 SLC22A8 Benzylpenicillin(b)
Estrone-3-sulfate (j,m)
Methotrexate (b,c,j,n)
Pravastatin(b,c)
MATE1, MATE-2K SLC47A1, SLC47A2 Metformin(o)
1-methyl-4-phenylpyridinium (MPP+)(o)
Tetraethylammonium (TEA)(o)
OCT2 SLC22A2 Metformin (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)

Transporter Gene Inhibitor
P-gp ABCB1 Cyclosporine(a)
Elacridar (GF120918)(b)
Ketoconazole(c)
Quinidine(d)
Reserpine(e)
Ritonavir(f)
Tacrolimus(f)
Valspodar (PSC833)(e)
Verapamil(d)
Zosuquidar (LY335979)
BCRP ABCG2 Elacridar (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, OAT3 SLC22A6, SLC22A8 Benzylpenicillin
Probenecid(f)
MATE1, MATE-2K SLC47A1, SLC47A2 Cimetidine(d,i)
Pyrimethamine
OCT2 SLC22A2 Cimetidine(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) (12/03/2019)

Transporter Gene Substrate
P-gp ABCB1 Dabigatran etexilate, digoxin, fexofenadine(e)
BCRP ABCG2 rosuvastatin, sulfasalazine
OATP1B1
OATP1B3		 SLCO1B1,
SLCO1B3		 asunaprevir, atorvastatin, bosentan, 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, SLC22A2 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).

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)

Transporter Gene Inhibitor
P-gp(a) ABCB1 amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil
BCRP ABCG2 curcumin, cyclosporine A, eltrombopag
OATP1B1, OATP1B3 SLCO1B1, SLCO1B3 atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir and ritonavir, rifampin (single dose), simeprevir
OAT1, OAT3 SLC22A6, SLC22A8 p-aminohippuric acid (PAH)(b), probenecid, teriflunomide
MATE1, MATE2-K SLC47A1, SLC47A2 cimetidine, 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.<. i="">
  • 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.

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