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CYP Enzymes
In vitro
In vitro marker reactions
In vitro selective inhibitors
In vitro inducers
Clinical index drugs
Clinical index substrates
Clinical index inhibitors
Clinical index inducers
Examples of clinical substrates, inhibitors, and inducers
Clinical substrates
Clinical inhibitors
Clinical inducers
Transporters
In vitro
In vitro substrates
In vitro inhibitors
Examples of clinical substrates, inhibitors and inducers
Clinical substrates
Clinical inhibitors

Table 1-1: Examples of in vitro marker reactions for P450-mediated metabolism

(9/26/2016)

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Enzyme

Marker reaction

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CYP1A2

Phenacetin O-deethylation, 7-Ethoxyresorufin-O-deethylation

CYP2B6

Efavirenz hydroxylation, Bupropion hydroxylation

CYP2C8

Paclitaxel 6-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 6-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

-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 CYP2C19and 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)

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Enzyme

Inducer*

CYP1A2

Omeprazole, Lansoprazole

CYP2B6

Phenobarbital

CYP2C8

Rifampicin

CYP2C9

Rifampicin

CYP2C19

Rifampicin

CYP3A4/5

Rifampicin

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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

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Database [Hachad et al. (2010), Hum Genomics, 5(1):61], and the list of references is
available here (/downloads/Drugs/DevelopmentApprovalProcess
/DevelopmentResources/DrugInteractionsLabeling/UCM518342.pdf).
(a)

We currently do not have sensitive index substrates for CYP2B6.

Also OATP1B1 substrate.
(c) Moderate sensitive substrates.
(d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects.
(b)

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 (/downloads/Drugs/DevelopmentApprovalProcess

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/DevelopmentResources/DrugInteractionsLabeling/UCM518343.pdf).
(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 (/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources

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/DrugInteractionsLabeling/UCM518350.pdf).
(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)

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Sensitive substrates

Moderate sensitive substrates

CYP1A2

alosetron, caffeine, duloxetine,

melatonin, ramelteon, tasimelteon,
theophylline, tizanidine

clozapine, pirfenidone, ramosetron

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, venlafaxine

amitriptyline, encainide, imipramine,

metoprolol, propafenone,
propranolol, tramadol, trimipramine,

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

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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)

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Strong inhibitors

Moderate inhibitors

Weak inhibitors

CYP1A2

ciprofloxacin, enoxacin,
fluvoxamine(a),
zafirlukast

methoxsalen, mexiletine
,oral contraceptives

acyclovir, allopurinol,
cimetidine,
peginterferon alpha-2a,
piperine, zileuton

CYP2B6

clopidogrel(b), tenofovir,
ticlopidine(c),
voriconazole(d)

CYP2C8

clopidogrel(b),
gemfibrozil(e)

deferasirox,
teriflunomide

telithromycin,
trimethoprim

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CYP2C9

amiodarone, felbamate,
fluconazole(f),
miconazole, piperine

diosmin, disulfiram,
fluvastatin,
fluvoxamine(a),
voriconazole

CYP2C19

fluconazole(f),
fluoxetine(g),
fluvoxamine(a),
ticlopidine

omeprazole,
voriconazole

CYP2D6

bupropion, fluoxetine(g),
paroxetine, quinidine(h),
terbinafine

cimetidine, cinacalcet,
duloxetine,
fluvoxamine(a),
mirabegron

abiraterone,
amiodarone, celecoxib,
cimetidine, clobazam,
cobicistat,
desvenlafaxine,
escitalopram, labetalol,
lorcaserin, ritonavir(h,i,j),
sertraline, vemurafenib

CYP3A

boceprevir, 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,
voriconazole

aprepitant, 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.

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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)

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Strong inducers
CYP1A2

Moderate inducers

Weak inducers

phenytoin(a) rifampin(b),
ritonavir(c), smoking,
teriflunomide

CYP2B6

carbamazepine(d)

efavirenz(e), rifampin(a),
ritonavir(c)

nevirapine

CYP2C8

rifampin(a)

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CYP2C9

aprepitant,
carbamazepine(d),
enzalutamide(f),
rifampin(a), ritonavir(c)

CYP2C19

rifampin(a), ritonavir(c)

efavirenz(e),
enzalutamide(f),
phenytoin(b)

CYP3A

carbamazepine(d),
enzalutamide(f), mitotane,
phenytoin(b), rifampin(a),
St. Johns wort(g)

bosentan, efavirenz,
etravirine, modafinil

armodafinil,
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.

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. Johns wort varies widely and is preparation-dependent.
(b)

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)

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Fexofenadine(b,c,d)
Loperamide
Quinidine

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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-17-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

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SLC22A8

Benzylpenicillin(b)
Estrone-3-sulfate (j,m)
Methotrexate (b,c,j,n)
Pravastatin(b,c)

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MATE1,
MATE-2K

SLC47A1,
SLC47A2

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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)

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Elacridar (GF120918)(b)
Ketoconazole(c)
Quinidine(d)

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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-17-glucuronide(b,e)
Estrone-3-sulfate (b,c)
Rifampicin
Rifamycin SV

OAT1, OAT3

MATE1,
MATE-2K

SLC22A6,
SLC22A8

Benzylpenicillin

SLC47A1,
SLC47A2

Cimetidine(d,i)

Probenecid(f)

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.

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(f)

Also an inhibitor of OATPs.

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.
(g)

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)
Transporter

Gene

Substrate

P-gp

ABCB1

dabigatran, digoxin, fexofenadine(e)

BCRP

ABCG2

rosuvastatin, 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,
SLC22A2

dofetilide, metformin

Note:
Criteria for selecting clinical substrates are as follows:

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P-gp: (1) AUC fold-increase2 with verapamil or quinidine co-administration and (2)
in vitro transport by P-gp expression systems, but not extensively metabolized.
BCRP: (1) AUC fold-increase2 with pharmacogenetic alteration of ABCG2
(421C>A) and (2) in vitro transport by BCRP expression systems.
OATP1B1/OATP1B3: (1) AUC fold-increase2 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-increase1.5 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).

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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.

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.
(b)In vitro

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:

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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

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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.

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