Human Intestinal Transport System
Substrates, Activators, & Inhibitors
 

Effects of Some Flavonoids on P-Glycoprotein


Competitive Inhibitors
Activators 
(Increase ATPase activity)
Unknown Effect
Apigenin
Chromones
Dimethyl-kaempferide +++
Flavone
Flavonone
Flavopiridol*
Genistin
Genistein (high concentration)
Heptamethoxyflavone**
Isoflavone
Kaempferol*
Naringin/ Naringenin (GFJ)
Nobiletin (weak inhibition)**
Quercetin* (decreased ATPase activity)
Tangeretin**		 Flavopyridol*
Galangin
Genistein
Kaempferol*
Quercetin*
 
 
 
 
 
 
 

 

 Acacetin (no effect ?)
Chrysin (no effect ?)
3,7-dihydroxyflavone (no effect?)
Diosmine/Diosmetin
Glucorhamnosyl-flavone
Isoflavone genistein
Rutin (no effect ?)
 
 
 
 
 

 
*Biphasic effect
**Present in Orange juice

 

P-Glycoproteins (P-gp's)

[ P-gp Substrates/ Inhibitors (Flavonoids Excluded) ]

Amiloride
Amiodarone
Amytriptyline (increased effect when co-administered with TNF-a)
Atorvastatin
Aureobasidin & analogues
B669
B-859-35 (R-enantiomere) and its major metabolite
Berrylium fluoride (BeFx)
Calmodulin inhibitors
Chloroquine
Chloropromazine
Clofazimine
Cremophor EL
Cyclosporin A (Reversibly increases the level of P-gp expression 2 folds after 48 hours exposure in LS 180 and DW-1 cell lines), FK 506, rapamycin, ascomycin
Daunorubicine, daunomycine, morpholine doxorubicine
Diltiazem (Reversibly increases the level of P-gp expression 4 folds after 48 hours exposure)
Dipyridamole
Erythromycine
Fluoroquinolones: fleroxacin, enoxacin, grepafloxacin, levofloxacin, norfloxacine
Glibenclamides & analogues
Gluconate salts
Gramicidin
Hydrocortisone
Itraconazole
Lidocaine
MS-209 (quinolone derivative)
PAK-104p
Phosphatidyl-choline
Pristinamycin Ia
Propafenone, Amiodarone
Propranolol (racemic)
Pyridine analogue
Quercetin 4'-b-glucoside
Quinine & quinidine, quinacrine, cinchonine
Ritonavir (Km = 5 mM) > Saquinavir > Nelfinavir >> Indinavir (Km = 20 mM) (controversial) 
SDZ PSC 833 (decreases ATPase activity) , SDZ 280-446
Synthetics isoprenoids
Talinolol
Tamoxifen and metabolites
Taxoid (Tetracyclic taxopine C & derivatives)
Terfenadine
TMP-substituted phenazines
Triton X100 (detergent)
Valinomycin, Verapamil*, nifedipine*, bepridil, nicardipine*, niguldipine (S-enantiomere), nitrendipine, trifluoperazine, felodipine
(* Reversibly increase the level of P-gp expression 6 folds after 48 hours expousre)
Vinblastine (Km = 20 mM), Vincristine, Vindesine

 
[ P-gp Substrates, but not Inhibitors ]

Actinomycin D
Adriamycin
Aldosterone
b-Lactam antibiotics- celiprolol, DMP 728, Adefovir
Benzo[a]pyrene
C6 NBD-glycosylceramide (short chain fatty acid)
C6 NBD-phosphatidyl choline (short chain fatty acid)
Calcein AM
Colchicine
Cyclic & linear Peptides: N-Acetyl-leucyl-norleucine, Valinomycin, Yeast a-factor pheromone 
Dexamethasone, Cortisol, Hydrocortisone
Digoxin (Km = 67 mM)
Emetine
Estradiol
Ethidium bromide
Etoposide (Km=200mM), Teniposide
7,12-dimethylbenz[a]anthracene
Fexofenadine
Fluo-3 (Calcium indicator)
Hoechst 33342
L-DOPA
Losartan
Metkephamid
Mithramycin
Mitomycin C
Morphine
Paclitaxel, Docetaxel
Phosphatidylcholine, Phosphatidylethanolamine
Propantheline
Puromycin
Rhodamine 123
Tc99m sestamibi
Topotecan

 
 
[ P-gp Inhibitors, but not substrates]

1,9-dideoxyforskolin
Acridine orange
AMPPNP, ATP-g-S, vanadate (both of them inhibit the use of ATP)
Antisense MDR1 oligonucleotides
Azidopine
Bergamottin (Ki = 45 mM)
C219 (internal epitope) , MRK16 (external epitope) = specific anti-Pgp Abs
Clarithromycin
Dimethyl-b-cyclodextrin
GF120918 (specific)
HAT, HDAc (modulate P-gp gene transcription, histones enzymes modificators)
Ivermectin +++
Ketoconazole
Lamellarin I and other derivatives
Local anaesthetics
LY335979 (specific) = Cyclopropyl-dibenzosuberane
Midazolam (concentrations > 100 mM)
Progesterone, RU 486, Megestrol acetate
Protein kinase C inhibitors: staurosporine (also decreases MDR1 gene expression), calphostine C, PKCa antisense cDNA
Reserpine
Surfactants
Testosterone
Vanadate (ATP hydrolysis inhibitor)
XR 9576
XR 9051

 
[ P-gp Activators ]

alpha-naphtyliso-thiocyanate
Anthracyclines
Bile duct ligation (in rats)
Dexamethasone
Doxorubicin and daunorubicin (?)
cf Flavonoids
Hoechst 33342 (slight stimulatory effect)
3-methyl-cholanthrene
Phorbol 12,13 dibutyrate (conc. of 1, 3 and 10 mM; also stimulates MDR1 gene expression) or diacylglycol = PKCa activators
Pyrrolinone bioisoesteres
Phenothiazines
Sodium Arsenite, sodium Butyrate
St John’s Wort herbal extract (hypericum perforatum)
Progesterone
Prazosin

Ratio affinity of 3A4/P-gp for their common inhibitors range from 1 to 125 (highly specific for CYP3A4)
 
 
 
 

MRPs -- Multidrug Resistance Proteins


MRP-1 Substrates
MRP-1 Inducers
MRP-1 Blockers
Actinomycine
C6 NBD-glycosylceramide (short chain fatty acid)
Calcein AM
Daunorubicin
Dinitrophenol
Glucuronid of 
    *Bilirubin (Km = 1.5 - 2.5 mM)
    *Doxorubicin 
    *Estradiol (Km = 2.9 mM)
    *Hyodeoxycholate
    *VP16
Glutathione conjugate of 
     *Aflatoxin B1 (Km = 0.2 mM)
     *C6-NBD-Phosphatidylserine
     *Chlorambucil 
       *Daunomycin (WP814)
     *Daunorubicin (WP811 & WP813)
     *Dinitrophenol (DNP-SG) (Km = 3.6 mM)
     *Doxorubicin
     *Prostaglandin A1 (Km = 28 mM)
     *LTC4
     *Maleic acid
Digoxin (?)
Fluo 3 (Km = 12 mM) 
LTC4, LTD4 (Km = 0.1 mM)
Methotrexate (Km = 50 mM)
N-ethylmaleimide-S-glutathione
Oxidized glutathion +++ (co-transported with anti-cancer drugs)
Para-aminohippurate (Km = 372 mM)
Vinblastine (?)		 Chlorambucil
Epirubicin
Zinc
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 Actinomycine
Arsenate
Benzbromarone
Cyclosporin A
Dipyridamole
Furosemide
Gamma-GS(naphtyl)cysteinyl-glycine diethyl ester
Genistein
Glutathion
Indomethacin (high concentration)
2K112993 (steroides)
LTC4
LTD4 receptor antagonist
MK571
MS209 (quinolone derivative)
Oxydized Glutathion, Azidophenylacyl 
PAK-104p
Penicillin G
Probenecid
Pyridine analogue
QCRL3 (MRP1 specific monoclonal antibody)
Quinidine
Rifampicin
RU 486
SDZ-PSC 833, SDZ 280-446
Sodium vanadate
Sulfinpyrazone
Verapamil
Vinblastine

 


 
 
 

MRP-2 Substrates
MRP-2 Inducers
MRP-2 Blockers
BCECF (2’, 7’-bis(2-carboxyethyl)-5(6)-carboxyfluorescein)
Bilirubin-diglucuronid (and other phase 2 biotransformation products) (Km = 0.7 - 0.9 mM)
BQ123 (cyclic pentapeptide, endothelin receptor antagonist)
Calcein AM
Chrysin
Cotransport of heavy metals and oxyanions with glutathione
CPT11 (irinotecan)
Digoxin (?)
DNP-SG (2,4-dinitrophenyl S-glutathione) (Km = 6.5 mM)
Endothelin I
Estradiol 17b-D-glucuronide (Km = 7.2 mM)
Furosemide
Genistin
Glutathione-S-S-glutathione
Glutathion-methylfluorescein
Grepafloxacin
HIV protease inhibitors
Indomethacin (also activator)
LTC4, LTD4 (Km = 1 mM)
Methotrexate
Nethylmaleimide-S-glutathione
PAH
Penicillin G (also activator)
Pravastatin
Probenecid
SN 38 (CPT11 active metabolite)
Sulfinpyrazone (also activator)
Sulfotaurolithocholic acid (STLC)
Telmisaltan (BIBR 277) & its glucuronide metabolite
Temocaprilat
Vinblastine (?)		 2-acetyl aminofluorene
Cisplatin
Dexamethasone
Quercetin
t-butyl hydroquinone
Cycloheximide
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 Bacalin
Benzbromarone (non-competitive)
BSO (Buthionine Sulfoximine)
BSP
Cefodizime (Ki = 10 mM)
CPT11
Cyclosporin A
E3040
Folinic acid (Ki = 100 mM)
Furosemide
Genistein
Glibenclamine
Glycyrrhizine
HIV protease inhibitors +++
Indocyanine Green
Indomethacin (high conc., Ki = 200 mM)
LTC4
LTD4 receptor antagonist
Methotrexate
MK-571
Ouabaine
Phenobarbital (decreases MRP2 expression)
Probenecid* (Ki = 44 mM)
Quinidine
Rifampicin
S-decyl glutathione
Sulfinpyrazone (high conc.)
Taxol
Telmisaltan (BIBR 277) & its glucuronide metabolite
Vinblastine

* The most potent MRP-2 inhibitor in vivo because of no or low protein-binding.

**Bile duct ligation (reduces protein expression)


 
 
 

MRP 3 Substrates :
 
 

 

 DNP-S-glutathione (Km = 5.7 mM, Vmax = 3.8 pmol/mg/min)
Glucuronide conjuguates: D-Glucuronide 17-b-estradiol (Km = 25.6 mM, Vmax = 75.6 pmol/mg/min)
Glycocholate (Km = 248 mM, Vmax = 183 pmol/mg/min) 
LTC4 (Km = 5.3 mM, Vmax = 20.2 pmol/mg/min)
Methotrexate (Km = 776 mM, Vmax = 288 pmol/mg/min)
Taurocholate
MRP 3 Inducers : a-naphtyliso thiocyanate, Bile duct ligation, Phenobarbital
MRP 3 Blockers: Methotrexate
MRP 6 Substrates : BQ123


 
 

hOATP Substrates and Inhibitors


OATP-A (Brain basolateral uptake transporter)
Substrates		 All the Statins (HMG-CoA reductase inhibitors) 
BQ-123
BSP-S-glutathione
Deltorphin II
DHEAS
DPDPE [D-penicillamine 2,5]-Enkephaline
DNP-S-glutathione (intracellular substrate for efflux)
Estradiol 17b-D-glucuronide
Extrone-3-sulfate
Fexofenadine (Km = 6 mM)
Glutathione-SH (intracellular substrate for efflux)
Glycocholate (Vmax = 4.2 pmol/mg-protein/min)
Methyl-S-glutathione
Monoglucuronosyl-bilirubin 
N-methylquinine
Ouabain
Peptidomimetics (HIV protease inhibitors (?))
PGE2
S-DHEA 
Taurocholate
Tetraiodothyronine
Triiodothyronine
OATP-B (Ubiquitous basolateral uptake transporter)
Substrates 		 BSP
Estrone-3-sulfate
DHEAS
OATP-C (Liver specific basolateral uptake transporter)
Substrates (reduced glutathione exchange) 		 BQ-123
Bromsulfophtalein (BSP) 
DHEAS, DPDPE
DNP-S-glutathione
Estradiol 17b-D-glucuronide 
Estrone-3-sulfate
Fexofenadine (Km = 32 mM, Vmax = 54 pmol/mg-protein/min))
LTC4 (glutathione-S-conjugate)
Ochratoxin A
PGE2
Pravastatin
Taurocholate and bile acids
Triiodothyronine, Tetraiodothyronine
OATP-8 (Liver specific basolateral uptake transporter) Substrates of OATP-A listed above except N-methylquinine and PGE2
Digoxin
LTC4

 
roatp1 & roatp2 Inhibitors  BSP
Corticosterone
Cyclosporin
DOCA (desoxycorticosterone)
Glibenclamide
Probenecid
Quinidine
Rifampin
Simvastatine
Tolbutamide
Verapamil
roatp1 Specific Inhibitors  Cerivastatine
Ibuprofen
Imipromine
Indocyanine Gray
Indomethacin
Provastatin
Warfarin
roatp2 Specific Inhibitors  Digoxine
DNP-S-glutathione
Quinine
"roatp1 or roatp2" (?) Inhibitors  Ketoconazole
Quinidine
Valspodar (SDZ-PSC 833)
hOATP Inhibitors
(with IC50 > 10 mM for fexofenadine transport)		 Ketoconazole (55%; percent inhibition at 10 mM)
Lovastatin (67%)
Nefinavir (62%)
Quinidine (57%)
Ritonavir (76%)
Saquinavir (75%)
Verapamil (50%)
 


 
 

Other Transporters and Their Substrates in Epithelial Cells


ASBT (Bile acid-Sodium cotransporter) Bile acids
BCRP
Breast Cancer Resistant Protein		 Rhodamine 123
Mitoxantrone
Daunorubicin
Doxorubicin
BSEP (also known as sister Pgp)
*Bile Salt Export Protein		 Bile salts such as taurocholate and taurocholate analogs (Km = 5 mM) (humans)
Taxol; Vinblastine
hOCT1
*Human Organic Cation Transporter (intestinal and renal tubule brush border, canalicular liver cell)		 Substrates:
Azidothymine (AZT)
Choline
2’ Deoxytubercidin
Tetraethylammonium (TEA)
Inhibitors: 
Indinavir (IC50 = 62 mM) 
Nefinavir (IC50 = 22 mM)
Ritonavir (IC50 = 5.2 mM)
Saquinavir (IC50 = 83 mM)
MCT
*Monocarboxylic acid CoTransporter (intestinal apical transporter)		 Acetic acid
Atorvastatin
Benzoic acid
Nicotinic acid
Pravastatin (Km = 15.2 mM)
Npt1
* Rat hepatocytic (canalicular) and renal apical transporter, Chlore-dependent		 Betalactam antibiotics
-- Reduced expression after bile duct ligation.
NTCP
* Human Na (sodium) Taurocholate Cotransporting Polypeptide		 Substrates: bile acids
hOCTN1
* Human Organic Cation Transpoter
Bidirectional multispecific; pH-dependent H+/ cation antiporter)
Present in the kidneys, liver, intestine, and cerebellum		 Substrates: Tetraethylammonium (TEA), carnithine 
Inhibitors (IC50 in mM): 
5-(N,N-dimethyl) amiloride (0.18)
1-methyl-4-phenylpyrildinum (MPP)
Cimetidine (1.54)
Desipramine (0.08)
Imipramine
Nicotime
Procainamide (0.86)
Tetraethylammonium (TEA: 0.96)
Verapamil
OCTN2
*Sodium-dependent renal carnithine transporter (apical tubular plasma membrane)
Present in testes, colon, kidneys and liver		 Substrates:
Acetyl-L-carnithine
Carnitine (Km = 22.1 mM) ++++ (carry a quaternary nitrogen)
Cephaloridine, Cefoselis, Cefepime, Cefluprenam (i.e. CIIG, and CIIIG)
Inhibitors/ Substrates:MPP, Pyrilamine, Quinidine, Tetraethylanmonium (TEA): Km = 215 mM, Varapamil 
Inhibitors:
Acetylcholine
Choline
Serotonine
TEA
 +++
Diphenhydramine
Lidocaine
PepT1
*Intestinal transporter (enterocyte brush border)		 Anionic cephalosporins (cephalothin)
Benzyl-penicillin, cephalexin and cephadroxil (zwitterion cephalosporins)
Small peptides
Valacyclovir, valganciclovir
PepT2 Benzyl-penicillin, Cephalexin and Cephadroxil (zwitterion cephalosporins)
*Kidney transporter (apical tubular plasma membrane)
Small peptides
SLGT 1 (Sodium-Glucose cotransporter) Glucose
SPNT 1 (Sodium-Purine Nucleoside transporter) Substrates:Uridine, Inosine
Inhibitors: Cytidine, Thymidine