|
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)
CYP |
Inhibitor (1)
Preferred |
Ki (µM) |
Inhibitor (1)
Acceptable |
Ki (µM) |
1A2 |
furafylline (2)
|
0.6-0.73 |
a -naphthoflavone |
0.01 |
2A6 |
tranylcypromine
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 |
2C8 |
montelukast
quercetin |
1.1 |
trimethoprim
gemfibrozil
rosiglitazone
pioglitazone |
32
69-75
5.6
1.7 |
2C9 |
sulfaphenazole |
0.3 |
fluconazole
fluvoxamine
fluoxetine |
7
6.4-19
18-41 |
2C19 |
|
|
ticlopidine
nootkatone |
1.2
0.5 |
2D6 |
quinidine |
0.027-0.4 |
|
|
2E1 |
|
|
diethyldithiocarbamate
clomethiazole
diallyldisulfide |
9.8-34
12
150 |
3A4/5 |
ketoconazole
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.
- 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.
- Furafylline and methoxsalen are mechanism-based inhibitors and should be pre-incubated before adding substrate.
- cDNA expressing microsomes from human lymphoblast cells.
- Supersomes, microsomal isolated from insect cells transfected with baculovirus containing CYP2B6.
- IC50 values.
- Specific time-dependent inhibitor.
Table 2. Preferred and acceptable chemical substrates for in vitro experiments*
(9/25/2006)
CYP |
Substrate Preferred |
Km (µM) |
Substrate Acceptable |
Km (µM) |
1A2 |
phenacetin-O-deethylation |
1.7-152 |
7-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-hydroxylation |
5.4-19 |
amodiaquine 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’-hydroxylation |
13-35 |
omeprazole 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
|
39-157 |
p-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. Chemical Inducers for In Vitro Experiments*
(5/1/2006)
CYP |
Inducer (1)
-Preferred |
Inducer Concentrations (µM) |
Fold Induction |
Inducer (1)
-Acceptable |
Inducer Concentrations (µM) |
Fold Induction |
1A2 |
omeprazole
ß-naphthoflavone(2)
3-methylcholanthrene |
25-100
33-50
1,2 |
14-24
4-23
6-26 |
lansoprazole |
10 |
10 |
2A6 |
dexamethasone |
50 |
9.4 |
pyrazole |
1000 |
7.7 |
2B6 |
phenobarbital |
500-1000 |
5-10 |
phenytoin |
50 |
5-10 |
2C8 |
rifampin |
10 |
2-4 |
phenobarbital |
500 |
2-3 |
2C9 |
rifampin |
10 |
3.7 |
phenobarbital |
100 |
2.6 |
2C19 |
rifampin |
10 |
20 |
|
|
|
2D6 |
none identified |
|
|
|
|
|
2E1 |
none identified |
|
|
|
|
|
3A4 |
rifampin(3)
|
10-50
|
4-31 |
phenobarbital(3)
phenytoin
rifapentine
troglitazone
taxol
dexamethasone(4) |
100-2000
50
50
10-75
4
33-250 |
3-31
12.5
9.3
7
5.2
2.9- 6.9 |
* Note that this is not an exhaustive list (created May 1,
2006).
- Except for the cases noted below, the following test substrates were used: CYP1A2, 7-ethoxyresorufin; CYP 2A6, coumarin; CYP2C9, tolbutamide, CYP2C19, S-mephenytoin; CYP3A4, testosterone.
- CYP1A2: 1 of 4 references for b -naphthoflavone used phenacetin.
- CYP3A4: 2 of 13 references for rifampin and 1 of 3 references for phenobarbital used midazolam.
- CYP3A4: 1 of the 4 references for dexamethasone used nifedipine.
In vivo
Table 4. Examples of in vivo substrate, inhibitor, and inducer for specific CYP enzymes for study (oral administration) (1) *
(5/1/2006)
CYP |
Substrate |
Inhibitor |
Inducer |
1A2 |
theophylline, caffeine |
fluvoxamine |
smokers versus non-smokers (2) |
2B6 |
efavirenz |
|
rifampin |
2C8 |
repaglinide, rosiglitazone |
gemfibrozil |
rifampin |
2C9 |
warfarin, tolbutamide |
fluconazole, amiodarone
(use of PM versus EM subjects) (3) |
rifampin |
2C19 |
omeprazole, esoprazole,
lansoprazole, pantoprazole |
omeprazole, fluvoxamine, moclobemide
(use of PM versus EM subjects) (3) |
rifampin |
2D6 |
desipramine, dextromethorphan, atomoxetine |
paroxetine, quinidine, fluoxetine
(use of PM versus EM subjects) (3) |
none identified |
2E1 |
chlorzoxazone |
disulfirum |
ethanol |
3A4/
3A5
|
midazolam, buspirone,
felodipine,
lovastatin, eletriptan, sildenafil, simvastatin, triazolam |
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin |
rifampin, carbamazepine |
* Note that this is not an exhaustive list (created May 1,
2006).
- 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.
- A clinical study can be conducted in smokers as compared to non-smokers (in lieu of an interaction study with an inducer), when appropriate.
- 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 CYP3A inhibitors
*(1)
(5/1/2006)
Strong CYP3A inhibitors |
Moderate CYP3A inhibitors |
Weak CYP3A inhibitors |
≥ 5-fold increase in AUC |
≥ 2 but <5-fold increase in AUC |
≥ 1.25 but <2-fold increase in AUC |
atazanavir, clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin |
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir,
grapefruit juice(a), verapami |
cimetidine |
* Note that this is not an exhaustive list (created May 1,
2006).
(1)
Please note the following:
- A strong inhibitor is one that caused a ≥ 5-fold increase in the plasma AUC values or more than 80% decrease in clearance of CYP3A substrates (not limited to midazolam, a sensitive CYP3A substrate) in clinical evaluations
- A moderate inhibitor is one that caused a ≥ 2- but < 5-fold increase in the AUC values or 50-80% decrease in clearance of sensitive CYP3A substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations.
- A weak inhibitor is one that caused a ≥ 1.25 - but < 2-fold increase in the AUC values or 20-50% decrease in clearance of sensitive CYP3A substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations
(a) The effect of grapefruit juice varies widely.
Table 6. Classification of inhibitors of other CYP enzymes * (1)
(5/1/2006)
Strong CYP1A2 inhibitors |
Moderate CYP1A2 inhibitors |
Weak CYP1A2 inhibitors |
fluvoxamine
|
ciprofloxacin
mexiletine
propafenone
zileuton
|
acyclovir
cimetidine
famotidine
norfloxacin
verapamil |
Strong CYP2C8 inhibitors |
Moderate CYP2C8 inhibitors |
Weak CYP2C8 inhibitors |
gemfibrozil |
|
trimethoprim |
Strong CYP2C9 inhibitors |
Moderate CYP2C9 inhibitors |
Weak CYP2C9 inhibitors |
|
amiodarone, fluconazole, oxandrolone |
sulfinpyrazone |
Strong CYP2C19 inhibitors |
Moderate CYP2C19 inhibitors |
Weak CYP2C19 inhibitors |
omeprazole |
|
|
Strong CYP2D6 inhibitors |
Moderate CYP2D6 inhibitors |
Weak CYP2D6 inhibitors |
fluoxetine, paroxetine, quinidine |
duloxetine, terbinafine |
amiodarone, sertraline |
* Note that this is not an exhaustive list (created May 1,
2006).
(1)
Please note the following:
- A strong inhibitor is one that caused a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance of CYP substrates (not limited to sensitive CYP substrate) in clinical evaluations
- A moderate inhibitor is one that caused a > 2- but < 5-fold increase in the AUC values or 50-80% decrease in clearance of sensitive CYP substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations.
- A weak inhibitor is one that caused a > 1.25 - but < 2-fold increase in the AUC values or 20-50% decrease in clearance of sensitive CYP substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations
Classification of Substrates
Table 7. Examples (1)
of sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic range
* (5/1/2006)
Sensitive CYP3A substrates (1) |
CYP3A Substrates with Narrow therapeutic range (2) |
budesonide, buspirone, eplerenone , eletriptan, felodipine, fluticasone, lovastatin, midazolam, saquinavir, sildenafil, simvastatin, triazolam, vardenafil |
alfentanil, astemizole(a), cisapride(a), cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine(a) |
* Note that this is not an exhaustive list (created May 1,
2006).
- Sensitive CYP3A substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a known CYP3A inhibitor.
- CYP3A substrates with narrow therapeutic range refers to drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of CYP3A inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
(a) Not available in the United States.
Table 8. Examples sensitive CYP substrates or CYP substrates with narrow therapeutic range
* (5/1/2006)
Sensitive CYP1A2 substrates (1) |
CYP1A2 substrates with narrow therapeutic range (2) |
duloxetine, alosetron |
theophylline, tizanidine |
Sensitive CYP2C8 substrates (1) |
CYP2C8 substrates with
narrow therapeutic range (2) |
repaglinide |
paclitaxel |
Sensitive CYP2C9 substrates (1) |
CYP2C9 substrates with
narrow therapeutic range (2) |
|
warfarin, phenytoin |
Sensitive CYP2C19 substrates (1) |
CYP2C19 substrates with
narrow therapeutic range (2) |
omeprazole |
s-mephenytoin |
Sensitive CYP2D6 substrates (1) |
CYP2D6 substrates with
narrow therapeutic range (2) |
desipramine |
thioridazine |
* Note that this is not an exhaustive list (created May 1,
2006).
- 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.
- CYP substrates with narrow therapeutic range refers to drugs whose exposure-response indicates that increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).
P-gp Transporters
Table 9. Acceptable In Vitro P-gp Substrates
* (5/1/2006)
|
|
Ratio** |
Drug |
Conc. Used
(µM) |
Caco-2 |
MDR1-
MDCK*** |
MDR1-
LLCPK*** |
Digoxin |
0.01-10 |
4-14 |
4 |
4 |
Loperamide |
1-10 |
2-5 |
|
3.4 |
Quinidine |
0.05 |
3 |
|
5 |
Vinblastine a |
0.004-10 |
2-18 |
> 9 b |
3 |
Talinolol |
30 |
26 |
|
|
* 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 10. In Vitro P-gp Inhibitors * (5/1/2006)
Inhibitor |
IC50 (µM) |
Ki (µM) |
Caco-2*
|
Caco-2*
|
MDCK- MDR1*
|
LLC-PK1 MDR1**
|
Cyclosporine A a |
1.3 |
0.5 |
2.2 |
1.3 |
Ketoconazole a |
1.2 |
|
|
5.3 |
LY335979 |
0.024 |
|
|
|
Nelfinavir a |
1.4 |
|
|
|
Quinidine b |
2.2 |
3.2 |
8.6 |
|
Ritonavir a |
3.8 |
|
|
|
Saquinavir a |
6.5 |
|
|
|
Tacrolimus |
0.74 |
|
|
|
Valspodar (PSC833) |
0.11 |
|
|
|
Verapamil |
2.1 |
8 |
15 |
23 |
Elacridar (GF120918) (GG 918) |
|
0.4 |
0.4 |
|
Reserpine |
|
1.4 |
11.5 |
|
* 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 11. Major human transporters * (1)
(5/1/2006)
Gene |
Aliases |
Tissue |
Substrate |
Inhibitor |
Inducer |
ABCB1 |
P-gp, MDR1 |
intestine, liver, kidney, brain, placenta, adrenal, testes |
digoxin, fexofenadine, indinavir, vincristine, colchicine. topotecan, paclitaxel |
ritonavir,
cyclosporine,
verapamil, erythromycin, ketocoanzole, itraconazole, quinidine, elacridar (GF120918) LY335979, valspodar (PSC 833) |
rifampin, St John’s Wort |
ABCB4 |
MDR3 |
liver |
digoxin, paclitaxel, vinblastine |
|
|
ABCB11 |
BSEP |
liver |
vinblastine |
|
|
ABCC1 |
MRP1 |
intestine, liver, kidney, brain |
adefovir, indinavir |
|
|
ABCC2 |
MRP2, CMOAT |
intestine, liver, kidney, brain |
indinavir, cisplatin, |
cyclosporine |
|
ABCC3 |
MRP3, CMOAT2 |
intestine, liver, kidney, placenta, adrenal |
etoposide, methotrexate, tenoposide |
|
|
ABCC4 |
MRP4 |
|
|
|
|
ABCC5 |
MRP5 |
|
|
|
|
ABCC6 |
MRP6 |
liver, kidney |
cisplatin, daunorubicin |
|
|
ABCG2 |
BCRP |
intestine, liver, breast, placenta |
daunorubicin, doxorubicin,
topotecan, rosuvastatin, sulfasalazine |
elacridar (GF120918) |
|
SLCO1B1 |
OATP1B1, OATP-C
OATP2 |
liver |
rifampin, rosuvastatin, methotrexate, pravastatin, thyroxine |
cyclosporine
rifampin |
|
SLCO1B3 |
OATP1B3, OATP8, |
liver |
digoxin, methotrexate, rifampin, |
|
|
SLCO2B1 |
SLC21A9, OATP-B |
intestine, liver, kidney, brain |
pravastatin |
|
|
SLC10A1 |
NTCP |
liver, pancreas |
rosuvastatin |
|
|
SLC10A2 |
ASBT |
ileum, kidney, biliary tract |
|
|
|
SLC15A1 |
PEPT1 |
intestine, kidney |
ampicillin, amoxicillin, captopril, valacyclovir |
|
|
SLC15A2 |
PEPT2 |
kidney |
ampicillin, amoxicillin, captopril, valacyclovir |
|
|
SLC22A1 |
OCT-1 |
liver |
acyclovir, amantadine, desipramine, ganciclovir
metformin |
disopyramide, midazolam, phenformin, phenoxy-benzamine quinidine,
quinine, ritonavir, verapamil |
|
SLC22A2 |
OCT2 |
kidney, brain |
amantadine,
cimetidine, memantine |
desipramine, phenoxy-benzamine quinine |
|
SLC22A3 |
OCT3 |
skeletal muscle, liver, placenta, kidney, heart |
cimetidine |
desipramine, prazosin, phenoxy-benzamine |
|
SLC22A4 |
OCTN1 |
kidney, skeletal muscle, placenta, prostate, heart |
quinidine, verapamil |
|
|
SLC22A5 |
OCTN2 |
kidney, skeletal muscle, prostate, lung, pancreas, heart, small intestine, liver |
quinidien, verapamil |
|
|
SLC22A6 |
OAT1 |
kidney, brain |
acyclovir, adefovir,
methotrexate, zidovudine |
probenecid, cefadroxil, cefamandole, cefazolin, |
|
SLC22A7 |
OAT2 |
liver, kidney |
zidovudine |
|
|
SLC22A8 |
OAT3 |
kidney, brain |
cimetidine, methotrexate, zidovudine |
probenecid, cefadroxil, cefamandole, cefazolin, |
|
* Note that this is not an exhaustive list (created May 1,
2006).
- 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.
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Date created: May 1, 2006
Date updated: October 11, 2006 |
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