Chemical: Drug
topotecan

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The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for topotecan

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs4148157 NC_000004.11:g.89020934G>A, NC_000004.12:g.88099782G>A, NG_032067.2:g.136541C>T, NM_001257386.1:c.1368-334C>T, NM_004827.2:c.1368-334C>T, XM_005263354.1:c.1368-334C>T, XM_005263354.2:c.1368-334C>T, XM_005263355.1:c.1368-334C>T, XM_005263355.2:c.1368-334C>T, XM_005263356.1:c.1362-334C>T, XM_005263356.2:c.1362-334C>T, XM_011532420.1:c.1368-334C>T, rs56715039
G > A
SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • TPT
  • TTC
  • Topotecan Hcl
  • Topotecan Hydrochloride
  • Topotecan Lactone
  • Topotecane [INN-French]
  • Topotecanum [INN-Latin]
  • topotecan
Trade Names
  • Hycamptamine
  • Hycamptin
  • Hycamtin
Brand Mixture Names

PharmGKB Accession Id

PA451729

Type(s):

Drug

Description

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

Source: Drug Bank

Indication

For 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.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Topotecan 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.

Source: Drug Bank

Pharmacology

Topotecan, 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.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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

Source: Drug Bank

Protein Binding

35%

Source: Drug Bank

Half-Life

2-3 hours

Source: Drug Bank

Toxicity

The primary anticipated complication of overdosage would consist of bone marrow suppression.

Source: Drug Bank

Route of Elimination

Renal 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%.

Source: Drug Bank

Chemical Properties

Chemical Formula

C23H23N3O5

Source: Drug Bank

Isomeric SMILES

CC[C@@]1(c2cc-3n(c(=O)c2COC1=O)Cc4c3nc5ccc(c(c5c4)CN(C)C)O)O

Source: OpenEye

Canonical SMILES

CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O

Source: Drug Bank

Average Molecular Weight

421.4458

Source: Drug Bank

Monoisotopic Molecular Weight

421.163770861

Source: Drug Bank

SMILES

CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O

Source: Drug Bank

InChI String

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

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
ABCG2 (source: Drug Bank)
TOP1 (source: Drug Bank)
TOP1MT (source: Drug Bank)

Drug Interactions

Interaction Description
tamoxifen - topotecan Tamoxifen may increase serum concentrations of oral Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
tamoxifen - topotecan Tamoxifen may increase serum concentrations of oral Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - amiodarone The p-glycoprotein inhibitor, Amiodarone, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - atorvastatin The p-glycoprotein inhibitor, Atorvastatin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - carboplatin Administration of Topotecan after Carboplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed. (source: Drug Bank)
topotecan - carvedilol The p-glycoprotein inhibitor, Carvedilol, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - cisplatin Administration of Topotecan after Cisplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed. (source: Drug Bank)
topotecan - clarithromycin The p-glycoprotein inhibitor, Clarithromycin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - cyclosporine The p-glycoprotein inhibitor, Cyclosporine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - darunavir The p-glycoprotein inhibitor, Darunavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - dipyridamole The p-glycoprotein inhibitor, Dipyridamole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - erythromycin The p-glycoprotein inhibitor, Erythromycin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - filgrastim Filgrastim may increase the adverse effects of Topotecan. Increased risk of prolonged neutropenia. Filgrastim should be administered at least 24 hours following Topotecan therapy. Monitor for signs and symptoms of neutropenia. (source: Drug Bank)
topotecan - gefitinib The BCRP/ABCG2 inhibitor, Gefitnib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Gefitinib is initiated, discontinued or dose changed. (source: Drug Bank)
topotecan - imatinib The BCRP/ABCG2 inhibitor, Imatinib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Imatinib is initiated, discontinued or dose changed. (source: Drug Bank)
topotecan - itraconazole The p-glycoprotein inhibitor, Itraconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - ketoconazole The p-glycoprotein inhibitor, Ketoconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - lapatinib The p-glycoprotein inhibitor, Lapatinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - lopinavir The p-glycoprotein inhibitor, Lopinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - mefloquine The p-glycoprotein inhibitor, Mefloquine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - natalizumab The immunosuppressant, Topotecan, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided. (source: Drug Bank)
topotecan - nelfinavir The p-glycoprotein inhibitor, Nelfinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - nicardipine The p-glycoprotein inhibitor, Nicardipine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - nilotinib The p-glycoprotein inhibitor, Nilotinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - oxaliplatin Administration of Topotecan after Oxaliplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed. (source: Drug Bank)
topotecan - pantoprazole The BCRP/ABCG2 inhibitor, Pantaprazole, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Pantaprazole is initiated, discontinued or dose changed. (source: Drug Bank)
topotecan - progesterone The p-glycoprotein inhibitor, Progesterone, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - propranolol The p-glycoprotein inhibitor, Propranolol, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - quinidine The p-glycoprotein inhibitor, Quinidine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - ranolazine The p-glycoprotein inhibitor, Ranolazine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - reserpine The p-glycoprotein inhibitor, Reserpine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - ritonavir The p-glycoprotein inhibitor, Ritonavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - saquinavir The p-glycoprotein inhibitor, Saquinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - sunitinib The p-glycoprotein inhibitor, Sunitinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - tacrolimus The p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - tamoxifen The p-glycoprotein inhibitor, Tamoxifen, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
topotecan - verapamil The p-glycoprotein inhibitor, Verapamil, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)
trastuzumab - topotecan Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. (source: Drug Bank)
verapamil - topotecan Verapamil, a p-glycoprotein inhibitor, may increase the concentration of Topotecan. Concomitant therapy should be avoided. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to topotecan: 11

No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant. Drug metabolism and disposition: the biological fate of chemicals. 2016. Roberts Jessica K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines. Pharmacogenomics. 2014. Brown Chad C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The Novel BCR-ABL and FLT3 Inhibitor Ponatinib Is a Potent Inhibitor of the MDR-Associated ATP-Binding Cassette Transporter ABCG2. Molecular cancer therapeutics. 2012. Sen Rupashree, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomic characterization of US FDA-approved cytotoxic drugs. Pharmacogenomics. 2011. Peters Eric J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenetics and genomics. 2011. Hodges Laura M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees. PloS one. 2011. Watson Venita Gresham, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Machine learning methods and docking for predicting human pregnane X receptor activation. Chemical research in toxicology. 2008. Khandelwal Akash, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica; the fate of foreign compounds in biological systems. 2008. Zhou S-F. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Improvement of the oral drug absorption of topotecan through the inhibition of intestinal xenobiotic efflux transporter, breast cancer resistance protein, by excipients. Drug metabolism and disposition: the biological fate of chemicals. 2007. Yamagata Tetsuo, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genomic signatures to guide the use of chemotherapeutics. Nature medicine. 2006. Potti Anil, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Development of a real-time in vivo transcription assay: application reveals pregnane X receptor-mediated induction of CYP3A4 by cancer chemotherapeutic agents. Molecular pharmacology. 2002. Schuetz Erin, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0007-4201-01
DrugBank:
DB01030
PDB:
TTC
KEGG Compound:
C11158
PubChem Compound:
60700
PubChem Substance:
46505204
606579
Drugs Product Database (DPD):
2231116
ChemSpider:
54705
HET:
TTC
Therapeutic Targets Database:
DAP000648
FDA Drug Label at DailyMed:
3c15da96-d309-4b93-f5aa-cfb52c25c174

Clinical Trials

These are trials that mention topotecan and are related to either pharmacogenetics or pharmacogenomics.

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NURSA Datasets

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No NURSA datasets available.

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Sources for PharmGKB drug information: DrugBank, PubChem.