Identification

Name
Rucaparib
Accession Number
DB12332
Type
Small Molecule
Groups
Approved, Investigational
Description

Rucaparib is a potent mammalian poly(ADP-ribose) polymerase (PARP) 1, 2 and 3 inhibitor with anticancer properties. PPAR is an enzyme that plays an essential role in DNA repair by activating response pathways and facilitating repair [2], and defects in these repair mechanisms have been demonstrated in various malignancies, including cancer. Regulation of repair pathways is critical in promoting necessary cell death. BRCA genes are tumor suppressor genes mediate several cellular process including DNA replication, transcription regulation, cell cycle checkpoints, apoptosis, chromatin structuring and homologous recombination (HR). Homologous recombination deficiency (HRD), along with PPAR inhibition, is a vulnerability that enhances the cell death pathway when the single mutations alone would permit viability. Ovarian cancer commonly possesses defects in DNA repair pathways such as HRD due to BRCA mutations or otherwise.

There are three main types of ovarian cancer: epithelial (90%), germ cell (5%) and sex cord stromal cell (5%). Epithelial ovarian, being the most common, fifth leading cause of cancer-related deaths in women in the United States. Advanced ovarian cancer particularly poses challenges due to reduced therapeutic response rates from standard platinum-based chemotherapy and overall survival rates. Rucaparib has shown to induce cytotoxicity in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes [Label]. Of all the BRCA1/2 mutations in ovarian cancer, most are due to germline mutations (18%), and approximately 7% represent somatic mutations acquired within the tumor [4].

The indication of rucaparib as an oral monotherapy in patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer was granted accelerated approval in 2016 for selected patients who have previously received greater than two lines of platinum-based therapy. It is currently marketed in the US under the brand name Rubraca that contains rucaparib camsylate as the active ingredient. The identification of patients who are eligible for rucaparib therapy is performed via in vitro diagnostic tests to detect the presence of a deleterious BRCA mutation (germline and/or somatic). The FDA-approved test qualitatively detects sequence alterations in BRCA1 and BRCA2 (BRCA1/2) genes. More information can be found on the FDA Website [9].

While rucaparib is indicated for deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer, there is evidence that its antitumor activity is also clinically effective against ovarian tumors with high homologous recombination deficiency (HRD) loss of heterozygosity (LOH) [4].

Structure
Thumb
Synonyms
Not Available
External IDs
AG-14447
Product Ingredients
IngredientUNIICASInChI Key
Rucaparib camsylate41AX9SJ8KO1859053-21-6INBJJAFXHQQSRW-STOWLHSFSA-N
Rucaparib phosphateH3M9955244459868-92-9FCCGJTKEKXUBFZ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RubracaTablet, film coated200 mg/1OralClovis Oncology, Inc.2016-12-19Not applicableUs
RubracaTablet, film coated250 mg/1OralClovis Oncology, Inc.2017-05-01Not applicableUs
RubracaTablet, film coated300 mg/1OralClovis Oncology, Inc.2016-12-19Not applicableUs
Categories
UNII
8237F3U7EH
CAS number
283173-50-2
Weight
Average: 323.371
Monoisotopic: 323.143390375
Chemical Formula
C19H18FN3O
InChI Key
HMABYWSNWIZPAG-UHFFFAOYSA-N
InChI
InChI=1S/C19H18FN3O/c1-21-10-11-2-4-12(5-3-11)18-14-6-7-22-19(24)15-8-13(20)9-16(23-18)17(14)15/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24)
IUPAC Name
6-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,10-diazatricyclo[6.4.1.0^{4,13}]trideca-1,4,6,8(13)-tetraen-9-one
SMILES
CNCC1=CC=C(C=C1)C1=C2CCNC(=O)C3=C2C(N1)=CC(F)=C3

Pharmacology

Indication

Indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib.

Associated Conditions
Pharmacodynamics

Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA [Label].

The effect of multiple doses of rucaparib on QTc interval was evaluated in an open-label single-arm study in 56 patients with solid tumors who were administered continuous doses of rucaparib ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean QTcF increase from baseline (90% confidence interval [CI]) in population pharmacokinetics estimated 95% percentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib twice daily was 14.9 msec (11.1-18.7 msec) [Label].

Mechanism of action

Poly (ADP-ribose) polymerase (PARP) enzymes play a role in DNA repair. PPAR-1 is responsible in repairing single stranded breaks (SSBs) in base excision repair (BER). PARP1 also functions in nonhomologous end-joining (NHEJ) regulation, chromatin remodeling and homologous recombination (HR) DNA repair pathways [2]. When PARP is inhibited, single-strand breaks become double-strand breaks, which are typically repaired via homologous recombination [2]. Pre-existing homologous recombination deficiency (HRD) may occur through mutations in the BRCA1 or BRCA2 genes, which confers persistant cell repair and growth in cancer cells.

Rucaparib is an inhibitor of PARP-1, PARP-2, and PARP-3. Via an inhibitory effect on the PARP enzymatic activity, rucaparib decreases the formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death [Label]. It is proposed that PARP inhibition specifically targets tumor cells with preexisting HRD, such as those cells possessing mutations in the BRCA1 or BRCA2 genes [4]. Rucaparib induces synthetic lethality by disrupting ingle- and double-strand repair pathways leading to tumor cell death. It is also suggested that PARP inhibition can lead to trapping of PARP-1 enzyme on damaged DNA, effectively preventing continuation of the DNA repair process; defective BRCA1 recruitment to damaged DNA; and activation of alternative DNA repair such as error-prone nonhomologous end joining (NHEJ) or alternative end joining pathways leading to mutations or chromosomal changes and ultimately cell death [4].

TargetActionsOrganism
APoly [ADP-ribose] polymerase 1
antagonist
Human
APoly [ADP-ribose] polymerase 2
antagonist
Human
APoly [ADP-ribose] polymerase 3
antagonist
Human
Absorption

Rucaparib demonstrates a linear pharmacokinetic properties over a dose range from 240 to 840 mg twice daily with time-independence and dose-proportionality. The mean steady-state rucaparib Cmax was 1940 ng/mL (54% coefficient of variation [CV]) and AUC0-12h was 16900 h⋅ng/mL (54% CV) at the approved recommended dosage. The time to reach the steady-state peak plasma concentration (Tmax) was 1.9 hours at the recommended dosage. The mean absolute bioavailability of rucaparib immediate-release tablet was 36% with a range from 30% to 45%. Following a high-fat meal, the Cmax was increased by 20% and AUC 0-24h was increased by 38%, and T max was delayed by 2.5 hours, as compared to dosing under fasted conditions [Label].

Volume of distribution

Following a single intravenous dose of 12mg to 40mg rucaparib, the steady-state volume of distribution was 113L to 262L [Label].

Protein binding

In vitro, the protein binding of rucaparib was 70% in human plasma at therapeutic concentrations. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83 [Label].

Metabolism

According to in vitro studies, rucaparib is primarily metabolized by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4 [Label].

Route of elimination

Fecal excretion was the major route of elimination, accounting for ≥ 79% of the total dose.

Half life

Following a single oral dose of 600mg rucaparib, the mean terminal half life (t1/2) was 17-19 hours [Label].

Clearance

Following continuous 600mg rucaparib administration orally twice daily, the apparent clearance ranges from 15.3 to 79.2 L/hour. The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg [Label].

Toxicity

According to a bacterial reverse mutation (Ames) test, rucaparib has shown to be mutagenic. It was also clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. Rucaparib has a genotoxic potential. Based on its mechanism of action and findings from animal studies, rucaparib can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of rucaparib [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Rucaparib.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Rucaparib.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Rucaparib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Rucaparib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Rucaparib.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Rucaparib.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Rucaparib.
6-Deoxyerythronolide BThe metabolism of Rucaparib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Rucaparib.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Rucaparib.
Food Interactions
Not Available

References

General References
  1. Nile DL, Rae C, Hyndman IJ, Gaze MN, Mairs RJ: An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma. BMC Cancer. 2016 Aug 11;16:621. doi: 10.1186/s12885-016-2656-8. [PubMed:27515310]
  2. Jenner ZB, Sood AK, Coleman RL: Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol. 2016 Jun;12(12):1439-56. doi: 10.2217/fon-2016-0002. Epub 2016 Apr 18. [PubMed:27087632]
  3. Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer R: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer. 2016 Mar 29;114(7):723-30. doi: 10.1038/bjc.2016.41. Epub 2016 Mar 22. [PubMed:27002934]
  4. Dockery LE, Gunderson CC, Moore KN: Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer. Onco Targets Ther. 2017 Jun 19;10:3029-3037. doi: 10.2147/OTT.S114714. eCollection 2017. [PubMed:28790837]
  5. CENTER FOR DRUG EVALUATION AND RESEARCH [Link]
  6. Daily med. [Link]
  7. FDA Label [Link]
  8. wikipedia [Link]
  9. FDA List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) [Link]
External Links
KEGG Drug
D10079
PubChem Compound
9931954
PubChem Substance
347828593
ChemSpider
8107584
BindingDB
50446130
ChEBI
134689
ChEMBL
CHEMBL1173055
PharmGKB
PA166163418
HET
RPB
Wikipedia
Rucaparib
PDB Entries
4bjc / 4rv6
FDA label
Download (344 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherNeoplasms1
1Active Not RecruitingOtherTumors, Solid1
1CompletedTreatmentAdvanced Solid Tumors1
1RecruitingOtherNeoplasms1
1RecruitingTreatmentAdvanced Solid Tumors1
1RecruitingTreatmentBRCA1 Gene Mutation / Brca2 Gene Mutation / Folate Receptor Alpha Positive / Platinum Resistant Ovarian Cancer / Recurrent Fallopian Tube Carcinoma / Recurrent Ovarian Carcinoma / Recurrent Primary Peritoneal Carcinoma / Recurrent Uterine Carcinosarcoma / Recurrent Uterine Corpus Carcinoma / Recurrent Uterine Serous Carcinoma1
1RecruitingTreatmentCancer, Breast1
1RecruitingTreatmentNeoplasms, Gynecologic1
1RecruitingTreatmentSolid Tumor, Unspecified, Adult1
1, 2Active Not RecruitingTreatmentAdvanced Solid Tumor With Evidence of Germline or Somatic BRCA / Cancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm1
1, 2Active Not RecruitingTreatmentCancer, Advanced / Solid Tumors and Hematologic Malignancy / Tumors, Solid1
1, 2Not Yet RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Biliary System Disorder / BRCA1 Gene Mutation / Brca2 Gene Mutation / Homologous Recombination Deficiency / PALB2 Gene Mutation / Pancreatic Adenocarcinoma Metastatic / Stage IV Colorectal Cancer AJCC v7 / Stage IV Pancreatic Cancer AJCC v6 and v7 / Stage IVA Colorectal Cancer AJCC v7 / Stage IVB Colorectal Cancer AJCC v71
1, 2Not Yet RecruitingTreatmentStage IV Non-Small Cell Lung Cancer1
1, 2RecruitingTreatmentAdvanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer1
1, 2RecruitingTreatmentEndometrial Cancers / Prostate Cancer1
2Active Not RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm / Ovarian Epithelial Cancer1
2Active Not RecruitingTreatmentCancer, Breast1
2CompletedTreatmentBrca1 Mutation Carrier / Brca2 Mutation Carrier / Cancer of the Ovary / Cancer, Breast1
2CompletedTreatmentMalignant Neoplasm of Pancreas / Pancreatic Ductal Adenocarcinoma1
2Not Yet RecruitingTreatmentBiliary Tract Cancer1
2Not Yet RecruitingTreatmentEndometrial Cancers1
2Not Yet RecruitingTreatmentMesothelioma, Malignant1
2Not Yet RecruitingTreatmentMetastatic Endometrial cancer1
2RecruitingTreatmentATM Gene Mutation / BRCA1 Gene Mutation / Brca2 Gene Mutation / Castration Levels of Testosterone / Castration-Resistant Prostate Carcinoma / Homologous Recombination Deficiency / Prostate Carcinoma Metastatic in the Bone / PSA Level Greater Than or Equal to Two / PSA Progression / Stage IV Prostate Adenocarcinoma AJCC v71
2RecruitingTreatmentAdenocarcinoma of the Gastro-oesophageal Junction / Adenocarcinoma of the Oesophagus / Adenocarcinoma of the Stomach1
2RecruitingTreatmentBladder Cancers / Muscle Invasive Bladder Cancer / Renal Pelvis Carcinoma / Transitional Cell Carcinoma / Ureter Carcinoma / Urethra Carcinoma / Urinary Bladder Carcinoma / Urothelial carcinoma ureter metastatic1
2RecruitingTreatmentCervical Cancers / Endometrial Cancers1
2RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer1
2RecruitingTreatmentMetastatic Hormone Refractory Prostate Cancer1
2RecruitingTreatmentProstate Cancer2
2WithdrawnTreatmentDiabetes Mellitus (DM) / Retinopathy, Diabetic1
3Active Not RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm1
3RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm / Ovarian Epithelial Cancer1
3RecruitingTreatmentComplete Response / Fallopian Tube Cancer / FIGO Stage III-IV / Newly Diagnosed / Ovarian Epithelial Cancer / Partial Response / Primary Peritoneal1
3RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral250 mg/1
Tablet, film coatedOral300 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8859562No2014-10-142031-08-04Us
US8143241No2012-03-272027-08-12Us
US6495541No2002-12-172020-01-10Us
US8754072No2014-06-172031-02-10Us
US9045487No2015-06-022031-02-10Us
US8071579No2011-12-062027-08-12Us
US7531530No2009-05-122024-07-23Us
US7351701No2008-04-012024-07-23Us
US9861638No2018-01-092031-02-10Us
US9987285No2015-08-172035-08-17Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1 mg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0114 mg/mLALOGPS
logP2.39ALOGPS
logP2.45ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)13.16ChemAxon
pKa (Strongest Basic)9.32ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area56.92 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity92.91 m3·mol-1ChemAxon
Polarizability35.19 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as 2-phenylindoles. These are indoles substituted at the 2-position with a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indoles
Direct Parent
2-phenylindoles
Alternative Parents
Phenylpyrroles / Benzazepines / 3-alkylindoles / Phenylmethylamines / Benzylamines / Aralkylamines / Azepines / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides
show 9 more
Substituents
2-phenylindole / Benzazepine / 2-phenylpyrrole / 3-alkylindole / Benzylamine / Phenylmethylamine / Aralkylamine / Azepine / Benzenoid / Aryl fluoride
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP1
Uniprot ID
P09874
Uniprot Name
Poly [ADP-ribose] polymerase 1
Molecular Weight
113082.945 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Nad+ adp-ribosyltransferase activity
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP2
Uniprot ID
Q9UGN5
Uniprot Name
Poly [ADP-ribose] polymerase 2
Molecular Weight
66205.31 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Nad+ adp-ribosyltransferase activity
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP3
Uniprot ID
Q9Y6F1
Uniprot Name
Poly [ADP-ribose] polymerase 3
Molecular Weight
60069.7 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
Inhibitor
Inducer
Curator comments
Inhibition of the enzyme is reversible.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Dockery LE, Gunderson CC, Moore KN: Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer. Onco Targets Ther. 2017 Jun 19;10:3029-3037. doi: 10.2147/OTT.S114714. eCollection 2017. [PubMed:28790837]
  2. Rucaparib - Drug Summary Prescribers Digital Reference [Link]
  3. Rupacarib [File]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
Inhibitor
Downregulator
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Rucaparib - Drug Summary Prescribers Digital Reference [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition is reversible.
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition is reversible.
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition is reversible.
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition is reversible.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Daily med. [Link]
  2. EMA Reports [Link]
  3. Rubraca [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Rucaparib is an inhibitos of P-gp efflux transporters with an IC50 value of 283 uM [FDA Label].
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Rucaparib is an inhibitor of BCRP with an IC50 value of 55uM [FDA Label].
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, Domchek SM, Balmana J, Drew Y, Chen LM, Safra T, Montes A, Giordano H, Maloney L, Goble S, Isaacson J, Xiao J, Borrow J, Rolfe L, Shapira-Frommer R: A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clin Cancer Res. 2017 Aug 1;23(15):4095-4106. doi: 10.1158/1078-0432.CCR-16-2796. Epub 2017 Mar 6. [PubMed:28264872]
  2. Rucaparib FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Rucaparib has been shown to only inhibit the MATE-2K transporter.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. Colombo I, Lheureux S, Oza AM: Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer. Drug Des Devel Ther. 2018 Mar 21;12:605-617. doi: 10.2147/DDDT.S130809. eCollection 2018. [PubMed:29606854]
  2. Rucaparib FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
The inhibition is moderate.
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Jenner ZB, Sood AK, Coleman RL: Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol. 2016 Jun;12(12):1439-56. doi: 10.2217/fon-2016-0002. Epub 2016 Apr 18. [PubMed:27087632]
  2. Dockery LE, Gunderson CC, Moore KN: Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer. Onco Targets Ther. 2017 Jun 19;10:3029-3037. doi: 10.2147/OTT.S114714. eCollection 2017. [PubMed:28790837]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition was observed at ultra-therapeutic concentration (300 µM) of rucaparib [FDA Label].
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition was observed at ultra-therapeutic concentration (300 µM) of rucaparib [FDA Label].
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition was observed at ultra-therapeutic concentration (300 µM) of rucaparib [FDA Label].
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition was observed at ultra-therapeutic concentration (300 µM) of rucaparib [FDA Label].
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Weak inhibition was observed at ultra-therapeutic concentration (300 µM) of rucaparib [FDA Label].
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da

Drug created on October 20, 2016 15:59 / Updated on November 22, 2018 14:48