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Istradefylline

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Identification

Summary

Istradefylline is a selective adenoside A2A receptor antagonist indicated in adjunct to levodopa and carbidopa for the treatment of Parkinson's Disease.

Brand Names
Nourianz
Generic Name
Istradefylline
DrugBank Accession Number
DB11757
Background

Istradefylline, or KW6002, was developed by Kyowa Hakko Kirin in Japan for the treatment of Parkinson's disease as an adjunct to standard therapy.2 Unlike standard dopaminergic therapies for Parkinson's, Istradefylline targets adenosine A2A receptors in the basal ganglia.2 This region of the brain is highly involved in motor control.2

Istradefylline is indicated as an adjunct treatment to levodopa and carbidopa for Parkinson's disease.8

This drug was first approved in Japan on 25 March 2013.2 Istradefylline was granted FDA approval on 27 August 2019.5

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
Weight
Average: 384.436
Monoisotopic: 384.179755269
Chemical Formula
C20H24N4O4
Synonyms
  • Istradefylline
External IDs
  • Kw 6002
  • KW-6002
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Pharmacology

Indication

Istradefylline is indicated in adjunct to levodopa and carbidopa in the treatment of Parkinson's disease.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofParkinson's disease••••••••••••
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Pharmacodynamics

Istradefylline is a selective adenosine A2A receptor inhibitor.1,2 It has a long duration of action as it is given once daily and has a half life of 64-69 hours.1,2,8 Patients taking this medication should be monitored for dyskinesia, hallucinations, and lack of impulse control.8 Consider dose reductions for these patients.8

Mechanism of action

Istradefylline is a selective adenosine A2A receptor inhibitor.1,2 These receptors are found in the basal ganglia, a region of the brain that suffers degeneration in Parkinson's disease, and is also significantly involved in motor control.2 A2A receptors are also expressed on GABAergic medium spiny neurons within the indirect striato-pallidal pathway.7 The GABAergic action of this pathway is thereby reduced.7 Istradefylline has 56 times the affinity for A2A receptors than A1 receptors.2

TargetActionsOrganism
AAdenosine receptor A2a
antagonist
Humans
NAdenosine receptor A1
antagonist
Humans
Absorption

Istradefylline reaches a Cmax of 181.1ng/mL with a Tmax of 2.0h and an AUC of 11,100ng*h/mL.1 M1, the primary active metabolite, reaches a Cmax of 4.34ng/mL with a Tmax of 3.5h.1 The M8 metabolite reaches a Cmax of 12.6ng/mL with a Tmax of 3.0h and an AUC of 610ng*h/mL.1

Volume of distribution

The apparent volume of distribution of istradefylline is 448-557L.1

Protein binding

Istradefylline is approximately 98% protein bound in plasma,1 mostly to serum albumin and alpha-1-acid glycoprotein.7

Metabolism

The primary metabolite found in urine is the active 4'-O-monodesmethyl istradefylline (M1).1 Istradefylline is metabolized mainly by CYP1A1, CYP3A4, and CYP3A5.1 CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6 also partly contribute the the metabolism of istradefylline.1 Other identified metabolites are 1-β-hydroxylated-4’-O-demethyl istradefylline (M2), 3’,4’-O-didemethyl istradefylline (M3), M1 sulfate conjugate (M4), M1 glucuronide (M5), 1-β-hydroxylated istradefylline (M8) and hydrogenated M3 (M10).7

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Route of elimination

A 3mg/kg oral dose given to male rats was 17.6% elminated in the urine and 68.3% eliminated in the feces.7 In urine, 5.31% of the total dose was the M3 metabolite and 1.96% of the total dose was the M1 metabolite.7 In feces, 30.60% of the total dose was the M3 metabolite, 9.34% of the total dose was the M1 metabolite, 8.33% of the total dose was the M10 metabolite, and 1.62% of the total dose was unchanged istradefylline.7

Half-life

The terminal elimination half life of istradefylline was 64-69 hours.1,2

Clearance

The apparent clearance of istradefylline is 4.1-6.0L/h.1

Adverse Effects
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Toxicity

The oral LD50 in mice is >300mg/kg.6

Patients experiencing an overdose may present with hallucinations, agitation, and dyskinesia.8 Treat patients by discontinuing istradefylline and administering supportive treatment.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
AbametapirThe serum concentration of Istradefylline can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Istradefylline can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Istradefylline.
AbirateroneThe serum concentration of Istradefylline can be increased when it is combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Istradefylline.
Food Interactions
  • Avoid St. John's Wort. St. John's Wort decreases istradefylline concentrations.
  • Take at the same time every day.
  • Take with or without food.

Products

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International/Other Brands
Nouriast
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NourianzTablet, film coated40 mg/1OralKyowa Kirin, Inc.2019-08-27Not applicableUS flag
NourianzTablet, film coated20 mg/1OralKyowa Kirin, Inc.2019-08-27Not applicableUS flag

Categories

ATC Codes
N04CX01 — Istradefylline
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
Xanthines
Alternative Parents
6-oxopurines / Dimethoxybenzenes / Alkaloids and derivatives / Styrenes / Phenoxy compounds / Anisoles / Pyrimidones / Alkyl aryl ethers / N-substituted imidazoles / Heteroaromatic compounds
show 8 more
Substituents
6-oxopurine / Alkaloid or derivatives / Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Dimethoxybenzene / Ether
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
2GZ0LIK7T4
CAS number
155270-99-8
InChI Key
IQVRBWUUXZMOPW-PKNBQFBNSA-N
InChI
InChI=1S/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+
IUPAC Name
8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
SMILES
[H]\C(=C(\[H])C1=CC(OC)=C(OC)C=C1)C1=NC2=C(N1C)C(=O)N(CC)C(=O)N2CC

References

Synthesis Reference

https://patents.google.com/patent/CN104974157A/en

General References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
  2. Dungo R, Deeks ED: Istradefylline: first global approval. Drugs. 2013 Jun;73(8):875-82. doi: 10.1007/s40265-013-0066-7. [Article]
  3. Takahashi M, Fujita M, Asai N, Saki M, Mori A: Safety and effectiveness of istradefylline in patients with Parkinson's disease: interim analysis of a post-marketing surveillance study in Japan. Expert Opin Pharmacother. 2018 Oct;19(15):1635-1642. doi: 10.1080/14656566.2018.1518433. Epub 2018 Oct 3. [Article]
  4. Kondo T, Mizuno Y: A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol. 2015 Mar-Apr;38(2):41-6. doi: 10.1097/WNF.0000000000000073. [Article]
  5. FDA News Release: Istradefylline Approval [Link]
  6. Cayman Chemicals: Istradefylline MSDS [Link]
  7. Pharmaceuticals and Medical Devices Agency Japan: Report on Istradefylline [Link]
  8. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
PubChem Compound
5311037
PubChem Substance
347828111
ChemSpider
4470574
BindingDB
50176050
RxNav
2199015
ChEBI
134726
ChEMBL
CHEMBL431770
ZINC
ZINC000003803921
PDBe Ligand
JQ9
Wikipedia
Istradefylline
PDB Entries
8gng

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
4Active Not RecruitingTreatmentParkinson's Disease (PD) / Tremor1somestatusstop reasonjust information to hide
3CompletedTreatmentIdiopathic Parkinson's Disease2somestatusstop reasonjust information to hide
3CompletedTreatmentParkinson's Disease (PD)7somestatusstop reasonjust information to hide
3TerminatedTreatmentParkinson's Disease (PD)1somestatusstop reasonjust information to hide
2CompletedTreatmentMovement Disorder Syndrome / Parkinson's Disease (PD)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral40 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7727993No2010-06-012023-01-28US flag
US7727994No2010-06-012023-01-18US flag
US7541363No2009-06-022024-11-13US flag
US8318201No2012-11-272027-09-05US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)189-193Not Available
boiling point (°C)601Not Available
water solubility0.5µg/mLNot Available
pKa0.78FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.182 mg/mLALOGPS
logP2.82ALOGPS
logP2.42Chemaxon
logS-3.3ALOGPS
pKa (Strongest Basic)-1.4Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area76.9 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity107.11 m3·mol-1Chemaxon
Polarizability42.28 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0009000000-cfde16c35bf1fb1d4741
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0009000000-1cd23f9a23c06f37fd2b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0009000000-cd6ccd5704add2cd3ab2
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0uec-1019000000-461e87b9328acc3cd8b7
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-02tl-0239000000-98c1b65355403ffb17b8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0019-2179000000-e751892c6c490494e249
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-223.4704105
predicted
DarkChem Lite v0.1.0
[M-H]-186.94373
predicted
DeepCCS 1.0 (2019)
[M+H]+223.2778105
predicted
DarkChem Lite v0.1.0
[M+H]+189.3393
predicted
DeepCCS 1.0 (2019)
[M+Na]+195.25182
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Adenosine receptor A2a
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor for adenosine (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity)
Specific Function
Alpha-actinin binding
Gene Name
ADORA2A
Uniprot ID
P29274
Uniprot Name
Adenosine receptor A2a
Molecular Weight
44706.925 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
  2. Dungo R, Deeks ED: Istradefylline: first global approval. Drugs. 2013 Jun;73(8):875-82. doi: 10.1007/s40265-013-0066-7. [Article]
Details2. Adenosine receptor A1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase
Specific Function
G protein-coupled adenosine receptor activity
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Dungo R, Deeks ED: Istradefylline: first global approval. Drugs. 2013 Jun;73(8):875-82. doi: 10.1007/s40265-013-0066-7. [Article]

Enzymes

Details1. Cytochrome P450 1A1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15-alpha and C16-alpha positions (PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15805301). Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation (PubMed:15041462, PubMed:18577768). Catalyzes the epoxidation of double bonds of certain PUFA (PubMed:15041462, PubMed:19965576, PubMed:20972997). Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system (PubMed:20972997). Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer (PubMed:15041462). May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195)
Specific Function
Arachidonic acid monooxygenase activity
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details2. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details3. Cytochrome P450 3A5
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
Specific Function
Aromatase activity
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details4. Cytochrome P450 3A Subfamily (Protein Group)
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Components:
NameUniProt ID
Cytochrome P450 3A4P08684
Cytochrome P450 3A43Q9HB55
Cytochrome P450 3A5P20815
Cytochrome P450 3A7P24462
References
  1. Dungo R, Deeks ED: Istradefylline: first global approval. Drugs. 2013 Jun;73(8):875-82. doi: 10.1007/s40265-013-0066-7. [Article]
Details5. Cytochrome P450 1A2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function
Aromatase activity
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58406.915 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details6. Cytochrome P450 2B6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
Specific Function
Anandamide 11,12 epoxidase activity
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details7. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details8. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function
(r)-limonene 6-monooxygenase activity
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details9. Cytochrome P450 2C18
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
CYP2C18
Uniprot ID
P33260
Uniprot Name
Cytochrome P450 2C18
Molecular Weight
55710.075 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]
Details10. Cytochrome P450 2D6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
Anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Mukai M, Uchimura T, Zhang X, Greene D, Vergeire M, Cantillon M: Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. J Clin Pharmacol. 2018 Feb;58(2):193-201. doi: 10.1002/jcph.1003. Epub 2017 Sep 7. [Article]

Carriers

Details1. Albumin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function
Antioxidant activity
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Albumin
Molecular Weight
69365.94 Da
References
  1. Pharmaceuticals and Medical Devices Agency Japan: Report on Istradefylline [Link]
Details2. alpha1-acid glycoprotein (Protein Group)
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
Specific Function
Not Available
Components:
NameUniProt ID
Alpha-1-acid glycoprotein 1P02763
Alpha-1-acid glycoprotein 2P19652
References
  1. Pharmaceuticals and Medical Devices Agency Japan: Report on Istradefylline [Link]

Transporters

Details1. ATP-dependent translocase ABCB1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
Abc-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Dungo R, Deeks ED: Istradefylline: first global approval. Drugs. 2013 Jun;73(8):875-82. doi: 10.1007/s40265-013-0066-7. [Article]
  2. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details2. Broad substrate specificity ATP-binding cassette transporter ABCG2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function
Abc-type xenobiotic transporter activity
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details3. Solute carrier organic anion transporter family member 1B1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function
Bile acid transmembrane transporter activity
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
  2. Pharmaceuticals and Medical Devices Agency Japan: Report on Istradefylline [Link]
Details4. Solute carrier organic anion transporter family member 1B3
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function
Bile acid transmembrane transporter activity
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details5. Solute carrier family 22 member 6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
Specific Function
Alpha-ketoglutarate transmembrane transporter activity
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details6. POU domain, class 2, transcription factor 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transcription factor that specifically binds to the octamer motif (5'-ATTTGCAT-3') (PubMed:2904654, PubMed:7859290). Regulates IL6 expression in B cells with POU2AF1 (By similarity). Regulates transcription in a number of tissues in addition to activating immunoglobulin gene expression (PubMed:2901913, PubMed:2904654). Modulates transcription transactivation by NR3C1, AR and PGR (PubMed:10480874)
Specific Function
Dna-binding transcription factor activity
Gene Name
POU2F2
Uniprot ID
P09086
Uniprot Name
POU domain, class 2, transcription factor 2
Molecular Weight
51208.51 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details7. Multidrug and toxin extrusion protein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
Specific Function
Antiporter activity
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]
Details8. Multidrug and toxin extrusion protein 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney
Specific Function
Antiporter activity
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Istradefylline Oral Tablets [Link]

Drug created at October 20, 2016 20:45 / Updated at February 21, 2021 18:53