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Identification
NameTopotecan
Accession NumberDB01030  (APRD00687)
TypeSmall Molecule
GroupsApproved, Investigational
Description

An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I. [PubChem]

Structure
Thumb
Synonyms
9-[(dimethylamino)Methyl]-10-hydroxy-(4S)-camptothecin
Topotecane
Topotecanum
External Identifiers
  • SKF-104864
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Act Topotecanpowder for solution1 mgintravenousActavis Pharma CompanyNot applicableNot applicableCanada
Act Topotecanpowder for solution4 mgintravenousActavis Pharma Company2015-11-17Not applicableCanada
Hycamtininjection, powder, lyophilized, for solution4 mg/4mLintravenousGlaxo Smith Kline Llc1996-06-07Not applicableUs
Hycamtincapsule1 mg/1oralGlaxo Smith Kline Llc2008-09-16Not applicableUs
Hycamtincapsule.25 mg/1oralGlaxo Smith Kline Llc2008-09-16Not applicableUs
Hycamtinpowder for solution4 mgintravenousNovartis Pharmaceuticals Canada Inc1997-06-18Not applicableCanada
Mylan-topotecan Hydrochloride for Injectionpowder for solution4 mgintravenousMylan Pharmaceuticals UlcNot applicableNot applicableCanada
PMS-topotecanpowder for solution4 mgintravenousPharmascience Inc2013-08-29Not applicableCanada
PMS-topotecanpowder for solution1 mgintravenousPharmascience IncNot applicableNot applicableCanada
Topotecaninjection1 mg/mLintravenousSandoz Inc2011-02-25Not applicableUs
Topotecaninjection, solution, concentrate1 mg/mLintravenousTeva Parenteral Medicines, Inc.2013-05-21Not applicableUs
Topotecaninjection, solution, concentrate1 mg/mLintravenousSagent Pharmaceuticals2014-12-15Not applicableUs
Topotecaninjection, solution, concentrate1 mg/mLintravenousHospira, Inc.2011-02-02Not applicableUs
Topotecan for Injectionpowder for solution4 mgintravenousSandoz Canada Incorporated2009-10-02Not applicableCanada
Topotecan for Injectionpowder for solution4 mgintravenousFresenius Kabi Canada Ltd2012-03-16Not applicableCanada
Topotecan Hydrochloride for Injectionpowder for solution4 mgintravenousAccord Healthcare Inc2011-06-27Not applicableCanada
Topotecan Hydrochloride for Injectionpowder for solution4 mgintravenousMylan Pharmaceuticals Ulc2013-06-112016-07-06Canada
Topotecan Hydrochloride for Injectionsolution1 mgintravenousAccord Healthcare Inc2013-11-21Not applicableCanada
Topotecan Hydrochloride for Injectionsolution1 mgintravenousHospira Healthcare Corporation2012-03-27Not applicableCanada
Topotecan Injectionsolution1 mgintravenousTeva Canada Limited2013-10-21Not applicableCanada
Topotecan Injectionsolution1 mgintravenousSandoz Canada Incorporated2014-02-05Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousPfizer Laboratories Div Pfizer Inc.2012-08-29Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousSun Pharmaceutical Industries Limited2015-09-02Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousBedford Laboratories2011-04-18Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousActavis Pharma, Inc.2015-01-05Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousSagent Pharmaceuticals2011-06-27Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousFresenius Kabi USA, LLC2010-11-29Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousSagent Pharmaceuticals2010-11-28Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/mLintravenousMylan Institutional LLC2012-08-29Not applicableUs
Topotecan Hydrochlorideinjection, powder, lyophilized, for solution4 mg/4mLintravenousAccord Healthcare, Inc.2013-07-01Not applicableUs
Topotecan Hydrochlorideinjection, powder, for solution4 mg/4mLintravenousThree Rivers Pharmaceuticals, LLC.2010-12-02Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Topotecan hydrochloride
119413-54-6
Thumb
  • InChI Key: DGHHQBMTXTWTJV-BQAIUKQQSA-N
  • Monoisotopic Mass: 457.1404486
  • Average Mass: 457.907
DBSALT000322
Categories
UNII7M7YKX2N15
CAS number123948-87-8
WeightAverage: 421.4458
Monoisotopic: 421.163770861
Chemical FormulaC23H23N3O5
InChI KeyInChIKey=UCFGDBYHRUNTLO-QHCPKHFHSA-N
InChI
InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
IUPAC Name
(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0²,¹¹.0⁴,⁹.0¹⁵,²⁰]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
SMILES
CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as camptothecins. These are heterocyclic compounds comprising a planar pentacyclic ring structure, that includes a pyrrolo[3,4-beta]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring).
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassCamptothecins
Sub ClassNot Available
Direct ParentCamptothecins
Alternative Parents
Substituents
  • Camptothecin
  • Hydroxyquinoline
  • Quinoline
  • Pyranopyridine
  • Benzylamine
  • Aralkylamine
  • Pyridinone
  • Benzenoid
  • Pyridine
  • Heteroaromatic compound
  • Tertiary alcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Lactone
  • Lactam
  • Carboxylic acid ester
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.
PharmacodynamicsTopotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.
Mechanism of actionTopotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding35%
Metabolism

Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.

Route of eliminationRenal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.
Half life2-3 hours
ClearanceNot Available
ToxicityThe primary anticipated complication of overdosage would consist of bone marrow suppression.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8911
Blood Brain Barrier-0.9659
Caco-2 permeable-0.6966
P-glycoprotein substrateSubstrate0.7918
P-glycoprotein inhibitor INon-inhibitor0.6121
P-glycoprotein inhibitor IINon-inhibitor0.9507
Renal organic cation transporterNon-inhibitor0.9
CYP450 2C9 substrateNon-substrate0.8844
CYP450 2D6 substrateNon-substrate0.8168
CYP450 3A4 substrateSubstrate0.6875
CYP450 1A2 substrateInhibitor0.5572
CYP450 2C9 inhibitorNon-inhibitor0.8305
CYP450 2D6 inhibitorNon-inhibitor0.8918
CYP450 2C19 inhibitorNon-inhibitor0.824
CYP450 3A4 inhibitorNon-inhibitor0.6464
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7184
Ames testNon AMES toxic0.6516
CarcinogenicityNon-carcinogens0.8504
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.0075 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9963
hERG inhibition (predictor II)Non-inhibitor0.8302
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral.25 mg/1
Capsuleoral1 mg/1
Injection, powder, lyophilized, for solutionintravenous4 mg/4mL
Powder for solutionintravenous1 mg
Injectionintravenous1 mg/mL
Injection, solution, concentrateintravenous1 mg/mL
Powder for solutionintravenous4 mg
Injection, powder, for solutionintravenous4 mg/4mL
Injection, powder, lyophilized, for solutionintravenous4 mg/mL
Solutionintravenous1 mg
Prices
Unit descriptionCostUnit
Hycamtin 4 mg vial1306.1USD vial
Hycamtin 1 mg capsule358.92USD capsule
Hycamtin 0.25 mg capsule89.73USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2103707 No2003-12-092012-02-07Canada
CA2103708 No2004-04-272012-02-07Canada
US5004758 No1993-05-282010-05-28Us
US5674872 No1995-04-072015-04-07Us
US8158645 No2004-12-102024-12-10Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point213-218 °CNot Available
water solubility1 mg/mlNot Available
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.861 mg/mLALOGPS
logP1.84ALOGPS
logP-0.36ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)8ChemAxon
pKa (Strongest Basic)9.83ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area103.2 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity115.02 m3·mol-1ChemAxon
Polarizability44.86 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Venkata Raghavendra Palle, Sekhar Nariyam, Lankeshwara Matti, “PROCESS FOR PREPARING TOPOTECAN.” U.S. Patent US20070149783, issued June 28, 2007.

US20070149783
General References
  1. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. [PubMed:9885371 ]
  2. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. [PubMed:8853931 ]
  3. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. [PubMed:9122737 ]
External Links
ATC CodesL01XX17
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelDownload (78.6 KB)
MSDSDownload (29.3 KB)
Interactions
Drug Interactions
Drug
AbirateroneThe serum concentration of Topotecan can be increased when it is combined with Abiraterone.
AmiodaroneThe serum concentration of Topotecan can be increased when it is combined with Amiodarone.
AtorvastatinThe serum concentration of Topotecan can be increased when it is combined with Atorvastatin.
AzithromycinThe serum concentration of Topotecan can be increased when it is combined with Azithromycin.
CarboplatinThe risk or severity of adverse effects can be increased when Carboplatin is combined with Topotecan.
CarvedilolThe serum concentration of Topotecan can be increased when it is combined with Carvedilol.
CisplatinThe risk or severity of adverse effects can be increased when Cisplatin is combined with Topotecan.
ClarithromycinThe serum concentration of Topotecan can be increased when it is combined with Clarithromycin.
ClozapineThe risk or severity of adverse effects can be increased when Topotecan is combined with Clozapine.
CobicistatThe serum concentration of Topotecan can be increased when it is combined with Cobicistat.
CrizotinibThe serum concentration of Topotecan can be increased when it is combined with Crizotinib.
CyclosporineThe serum concentration of Topotecan can be increased when it is combined with Cyclosporine.
DabrafenibThe serum concentration of Topotecan can be increased when it is combined with Dabrafenib.
DaclatasvirThe serum concentration of Topotecan can be increased when it is combined with Daclatasvir.
DarunavirThe serum concentration of Topotecan can be increased when it is combined with Darunavir.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Topotecan.
DipyridamoleThe serum concentration of Topotecan can be increased when it is combined with Dipyridamole.
DronedaroneThe serum concentration of Topotecan can be increased when it is combined with Dronedarone.
EliglustatThe serum concentration of Topotecan can be increased when it is combined with Eliglustat.
EltrombopagThe serum concentration of Topotecan can be increased when it is combined with Eltrombopag.
ErythromycinThe serum concentration of Topotecan can be increased when it is combined with Erythromycin.
FilgrastimThe risk or severity of adverse effects can be increased when Filgrastim is combined with Topotecan.
Filgrastim-sndzThe risk or severity of adverse effects can be increased when Filgrastim-sndz is combined with Topotecan.
FlibanserinThe serum concentration of Topotecan can be increased when it is combined with Flibanserin.
FosphenytoinThe serum concentration of Topotecan can be decreased when it is combined with Fosphenytoin.
GefitinibThe serum concentration of Topotecan can be increased when it is combined with Gefitinib.
IbrutinibThe serum concentration of Topotecan can be increased when it is combined with Ibrutinib.
ImatinibThe serum concentration of Topotecan can be increased when it is combined with Imatinib.
ItraconazoleThe serum concentration of Topotecan can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Topotecan can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Topotecan can be increased when it is combined with Ketoconazole.
LapatinibThe serum concentration of Topotecan can be increased when it is combined with Lapatinib.
LeflunomideThe risk or severity of adverse effects can be increased when Topotecan is combined with Leflunomide.
LomitapideThe serum concentration of Topotecan can be increased when it is combined with Lomitapide.
MefloquineThe serum concentration of Topotecan can be increased when it is combined with Mefloquine.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Topotecan.
MirabegronThe serum concentration of Topotecan can be increased when it is combined with Mirabegron.
NatalizumabThe risk or severity of adverse effects can be increased when Topotecan is combined with Natalizumab.
NicardipineThe serum concentration of Topotecan can be increased when it is combined with Nicardipine.
NilotinibThe serum concentration of Topotecan can be increased when it is combined with Nilotinib.
OxaliplatinThe risk or severity of adverse effects can be increased when Oxaliplatin is combined with Topotecan.
PantoprazoleThe serum concentration of Topotecan can be increased when it is combined with Pantoprazole.
PhenytoinThe serum concentration of Topotecan can be decreased when it is combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Topotecan.
ProgesteroneThe serum concentration of Topotecan can be increased when it is combined with Progesterone.
PropranololThe serum concentration of Topotecan can be increased when it is combined with Propranolol.
QuinidineThe serum concentration of Topotecan can be increased when it is combined with Quinidine.
QuinineThe serum concentration of Topotecan can be increased when it is combined with Quinine.
RanolazineThe serum concentration of Topotecan can be increased when it is combined with Ranolazine.
ReserpineThe serum concentration of Topotecan can be increased when it is combined with Reserpine.
RitonavirThe serum concentration of Topotecan can be increased when it is combined with Ritonavir.
RoflumilastRoflumilast may increase the immunosuppressive activities of Topotecan.
RolapitantThe serum concentration of Topotecan can be increased when it is combined with Rolapitant.
SaquinavirThe serum concentration of Topotecan can be increased when it is combined with Saquinavir.
SimeprevirThe serum concentration of Topotecan can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Topotecan.
SunitinibThe serum concentration of Topotecan can be increased when it is combined with Sunitinib.
TacrolimusThe serum concentration of Topotecan can be increased when it is combined with Tacrolimus.
TamoxifenThe serum concentration of Topotecan can be increased when it is combined with Tamoxifen.
TelaprevirThe serum concentration of Topotecan can be increased when it is combined with Telaprevir.
TeriflunomideThe serum concentration of Topotecan can be increased when it is combined with Teriflunomide.
TofacitinibTopotecan may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Topotecan.
VandetanibThe serum concentration of Topotecan can be increased when it is combined with Vandetanib.
VemurafenibThe serum concentration of Topotecan can be increased when it is combined with Vemurafenib.
VerapamilThe serum concentration of Topotecan can be increased when it is combined with Verapamil.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Poly(a) rna binding
Specific Function:
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphot...
Gene Name:
TOP1
Uniprot ID:
P11387
Molecular Weight:
90725.19 Da
References
  1. Schmidt F, Rieger J, Wischhusen J, Naumann U, Weller M: Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage. Eur J Pharmacol. 2001 Jan 19;412(1):21-5. [PubMed:11166732 ]
  2. strel'tsov SA, Mikheikin AL, Nechipurenko IuD: [Interaction of topotecan--a DNA topoisomerase I inhibitor--with dual-stranded polydeoxyribonucleotides. II. Formation of a complex containing several DNA molecules in the presence of topotecan]. Mol Biol (Mosk). 2001 May-Jun;35(3):442-50. [PubMed:11443926 ]
  3. Streltsov SA: Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. J Biomol Struct Dyn. 2002 Dec;20(3):447-54. [PubMed:12437383 ]
  4. Zhang J, Pu SP, Zhou YJ: [Preliminary study of apoptosis of human hepatocarcinoma cell line HepG2 induced by topotecan]. Ai Zheng. 2002 Dec;21(12):1305-9. [PubMed:12520736 ]
  5. Aisner J, Musanti R, Beers S, Smith S, Locsin S, Rubin EH: Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial. Clin Cancer Res. 2003 Jul;9(7):2504-9. [PubMed:12855624 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. [PubMed:9885371 ]
  8. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. [PubMed:8853931 ]
  9. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. [PubMed:9122737 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function:
Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosy...
Gene Name:
TOP1MT
Uniprot ID:
Q969P6
Molecular Weight:
69871.39 Da
References
  1. Kosovsky MJ, Soslau G: Immunological identification of human platelet mitochondrial DNA topoisomerase I. Biochim Biophys Acta. 1993 Jun 24;1164(1):101-7. [PubMed:8390858 ]
3. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
intercalation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L: The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. [PubMed:12426403 ]
  2. Pourquier P, Takebayashi Y, Urasaki Y, Gioffre C, Kohlhagen G, Pommier Y: Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1885-90. [PubMed:10677551 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitorinducer
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004 Apr 1;64(7):2333-7. [PubMed:15059881 ]
  2. Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH: Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001 Apr;7(4):935-41. [PubMed:11309344 ]
  3. Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T: Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003 Jan;2(1):105-12. [PubMed:12533678 ]
  4. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999 Sep 15;59(18):4559-63. [PubMed:10493507 ]
  5. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. [PubMed:11036110 ]
  6. Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH: Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 2003 Mar 15;63(6):1339-44. [PubMed:12649196 ]
  7. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. [PubMed:15313923 ]
  8. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. doi: 10.1158/0008-5472.CAN-09-4264. Epub 2010 May 11. [PubMed:20460504 ]
  9. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. doi: 10.1158/0008-5472.CAN-09-0700. Epub 2009 Jun 30. [PubMed:19567673 ]
  10. Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E: The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000 Apr 29;271(1):42-6. [PubMed:10777678 ]
  11. Ishii M, Iwahana M, Mitsui I, Minami M, Imagawa S, Tohgo A, Ejima A: Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anticancer Drugs. 2000 Jun;11(5):353-62. [PubMed:10912951 ]
  12. Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC: BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem Pharmacol. 2000 Sep 15;60(6):831-7. [PubMed:10930538 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
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
Molecular Weight:
141477.255 Da
References
  1. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. [PubMed:15180340 ]
  2. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. doi: 10.1158/0008-5472.CAN-09-4264. Epub 2010 May 11. [PubMed:20460504 ]
  3. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. doi: 10.1158/0008-5472.CAN-09-0700. Epub 2009 Jun 30. [PubMed:19567673 ]
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Drug created on June 13, 2005 07:24 / Updated on August 24, 2016 01:51