DT-Web

DB01073 - Fludarabine


Identification
Name Fludarabine
Accession Number DB01073 (APRD00594)
Type small molecule
Description Fludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies. [Wikipedia]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 365.2117
Groups approved
Monoisotopic Weight 365.053662512
Pharmacology
Indication For the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen
Mechanism of action Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Absorption Bioavailability is 55% following oral administration.
Protein binding 19-29%
Biotransformation Not Available
Route of elimination Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Dipyridamole Dipyridamole may decrease the effect of fludarabine.
Pentostatin Unacceptable pulmonary toxicity
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions
  • Take without regard to meals.
  • Food slightly increases product bioavailability.

Targets


Ribonucleoside-diphosphate reductase large subunit
Name Ribonucleoside-diphosphate reductase large subunit
Gene Name RRM1
Pharmacological action yes
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. - Pubmed
  • Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. - Pubmed
DTHybrid score 0.7512
DNA polymerase alpha catalytic subunit
Name DNA polymerase alpha catalytic subunit
Gene Name POLA1
Pharmacological action yes
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. - Pubmed
  • Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. - Pubmed
  • Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. - Pubmed
DTHybrid score 0.7148
DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions incorporation into and destabilization
References
  • Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. - Pubmed
DTHybrid score Not Available
Deoxycytidine kinase
Name Deoxycytidine kinase
Gene Name DCK
Pharmacological action yes
Actions agonist
References
  • Jordheim LP, Galmarini CM, Dumontet C: [Metabolism, mechanism of action and resistance to cytotoxic nucleoside analogues] Bull Cancer. 2005 Mar;92(3):239-48. - Pubmed
  • Yao L, Xu W, Fan L, Miao KR, Wu YJ, Qiao C, Zhu DX, Zhu HY, Liu P, Li JY: [Correlation of deoxycytidine kinase gene expression with fludarabine resistance in patients with chronic lymphocytic leukemia] Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Feb;18(1):36-9. - Pubmed
  • Zhang Y, Secrist JA 3rd, Ealick SE: The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation. Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006 Jan 18. - Pubmed
DTHybrid score 0.9482

Transporters


Equilibrative nucleoside transporter 1
Name Equilibrative nucleoside transporter 1
Gene Name SLC29A1
Actions substrate
References
  • Santini D, Vincenzi B, Fratto ME, Perrone G, Lai R, Catalano V, Cass C, Ruffini PA, Spoto C, Muretto P, Rizzo S, Muda AO, Mackey JR, Russo A, Tonini G, Graziano F: Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer. J Cell Physiol. 2010 May;223(2):384-8. - Pubmed
DTHybrid score 0.542
Solute carrier family 28 member 3
Name Solute carrier family 28 member 3
Gene Name SLC28A3
Actions Not Available
References
  • Badagnani I, Chan W, Castro RA, Brett CM, Huang CC, Stryke D, Kawamoto M, Johns SJ, Ferrin TE, Carlson EJ, Burchard EG, Giacomini KM: Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J. 2005;5(3):157-65. - Pubmed
DTHybrid score 0.507

Predictions


Id Partner name Gene Name Score
6083 Deoxyguanosine kinase, mitochondrial DGUOK 0.1744
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.1193
3755 Nucleoside-specific channel-forming protein tsx precursor tsx 0.1165
3611 Cytidine deaminase cdd 0.1097
3707 Cytidine deaminase cdd 0.1097
4211 Cytidine deaminase CDA 0.1097
6112 DNA polymerase epsilon subunit 3 POLE3 0.1015
6111 DNA polymerase epsilon subunit 4 POLE4 0.1015
6108 Ribonucleoside-diphosphate reductase subunit M2 B RRM2B 0.1014
6110 DNA polymerase epsilon subunit 2 POLE2 0.1014
6109 DNA polymerase epsilon catalytic subunit A POLE 0.1013
3957 Adenosine deaminase ADA 0.0993
3690 Class B acid phosphatase precursor aphA 0.0952
24 Thymidylate synthase TMP1 0.0913
359 Thymidylate synthase TYMS 0.0913
2626 Thymidylate synthase thyA 0.0913
2729 Thymidylate synthase thyA 0.0913
5352 Thymidylate synthase THYA 0.0913
702 UMP-CMP kinase CMPK1 0.0846
277 Purine nucleoside phosphorylase PNP 0.08
2870 Purine nucleoside phosphorylase punA 0.08
2945 Purine nucleoside phosphorylase punA 0.08
4659 Purine nucleoside phosphorylase TM_1596 0.08
4825 Purine nucleoside phosphorylase TTHA1435 0.08
6148 Multidrug resistance-associated protein 7 ABCC10 0.0752
4218 Ribonucleoside-diphosphate reductase M2 subunit RRM2 0.0747
6021 Adenosine kinase ADK 0.069
1064 DNA (cytosine-5)-methyltransferase 1 DNMT1 0.0636
6145 Solute carrier family 22 member 1 SLC22A1 0.0621
311 RNA-directed RNA polymerase catalytic subunit PB1 0.0576
752 Large structural protein L 0.0576
4119 Cytochrome P450 2D6 CYP2D6 0.0555
6144 Solute carrier family 22 member 2 SLC22A2 0.0518
289 Cytosolic purine 5'-nucleotidase NT5C2 0.0499
508 Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 ENPP1 0.0447
1043 Trifunctional purine biosynthetic protein adenosine-3 [Includes: Phosphoribosylamine--glycine ligase GART 0.0431
838 Inosine-5'-monophosphate dehydrogenase 1 IMPDH1 0.0384
2287 Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase ATIC 0.0368
1729 Solute carrier family 22 member 6 SLC22A6 0.0362
390 Adenosine A3 receptor ADORA3 0.0339
1830 5'-nucleotidase NT5E 0.0338
268 Adenosine A2b receptor ADORA2B 0.0323
1588 Multidrug resistance protein 1 ABCB1 0.0323
125 DNA polymerase beta POLB 0.0316
87 Hypoxanthine-guanine phosphoribosyltransferase HPRT1 0.0313
6136 Multidrug resistance-associated protein 5 ABCC5 0.0308
1405 Thiopurine S-methyltransferase TPMT 0.03
2164 Multidrug resistance-associated protein 4 ABCC4 0.0296
365 Dihydrofolate reductase DHFR 0.0273
2381 Dihydrofolate reductase DFR1 0.0273
2833 Dihydrofolate reductase Not Available 0.0273
2931 Dihydrofolate reductase folA 0.0273
3544 Dihydrofolate reductase folA 0.0273
3682 Dihydrofolate reductase folA 0.0273
6642 Dihydrofolate reductase folA 0.0273
6756 Dihydrofolate reductase dfrA 0.0273
6020 Aldehyde oxidase AOX1 0.0263
3947 Xanthine dehydrogenase/oxidase XDH 0.0236
16 Adenosine A1 receptor ADORA1 0.0236
1178 Adenosine A2a receptor ADORA2A 0.0236
2251 Thymidylate kinase tmk 0.023
2254 Thymidylate kinase DTYMK 0.023
3522 Thymidylate kinase tmk 0.023
3478 Glucose-1-phosphate thymidylyltransferase rmlA 0.0225
4277 Glucose-1-phosphate thymidylyltransferase rmlA 0.0225
2257 Uridine phosphorylase udp 0.0215
5132 Uridine phosphorylase udp 0.0215
509 Thymidine kinase TK 0.0214
570 Thymidine kinase TK 0.0214
2559 Thymidine kinase TK 0.0214
3430 Thymidine kinase tdk 0.0214
3518 Thymidine kinase TK 0.0214
5301 Thymidine kinase tdk 0.0214
5771 Thymidine kinase ORF36 0.0214
7009 Thymidine kinase ORF36 0.0214
4512 Cytochrome P450 3A4 CYP3A4 0.0201
6143 Solute carrier family 22 member 7 SLC22A7 0.0192
6031 Cytochrome P450 3A43 CYP3A43 0.019
6142 Solute carrier family 22 member 8 SLC22A8 0.0182
4757 Cytochrome P450 2C9 CYP2C9 0.0148
6107 Cytochrome P450 3A7 CYP3A7 0.014
4118 Cytochrome P450 3A5 CYP3A5 0.0132
342 P protein [Includes: DNA-directed DNA polymerase P 0.0099
612 P protein [Includes: DNA-directed DNA polymerase P 0.0099
4226 Uridine phosphorylase 2 UPP2 0.0094
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0091
677 Choline-phosphate cytidylyltransferase A PCYT1A 0.0088
4225 Uridine phosphorylase 1 UPP1 0.0085
5626 Nucleoside diphosphate kinase B NME2 0.0079
413 Amidophosphoribosyltransferase PPAT 0.0077
2515 Amidophosphoribosyltransferase purF 0.0077
3714 Amidophosphoribosyltransferase purF 0.0077
5294 Nucleoside diphosphate kinase A NME1 0.007
3639 Thymidine phosphorylase deoA 0.007
3936 Thymidine phosphorylase TYMP 0.007
267 Plasminogen activator inhibitor 1 SERPINE1 0.0067
1302 Dihydropyrimidine dehydrogenase [NADP+] DPYD 0.0062
6221 Steroid hormone receptor ERR1 ESRRA 0.0059
3917 Methylenetetrahydrofolate reductase MTHFR 0.0057
4924 Cytochrome P450 2C8 CYP2C8 0.0054
1457 Long-chain-fatty-acid--CoA ligase 4 ACSL4 0.0052
6147 Solute carrier family 22 member 3 SLC22A3 0.0046
3809 Estrogen-related receptor gamma ESRRG 0.0045
6177 UDP-glucuronosyltransferase 1-10 UGT1A10 0.0045
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.0045
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0041
862 Multidrug resistance-associated protein 1 ABCC1 0.004
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0038
5718 Cytochrome P450 2A6 CYP2A6 0.0037
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0036
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0034
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0033
587 Serum albumin ALB 0.0033
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0033
238 Peroxisome proliferator-activated receptor gamma PPARG 0.0032
776 Bile salt export pump ABCB11 0.0032
3811 Cytochrome P450 19A1 CYP19A1 0.0032
4200 Cytochrome P450 1A2 CYP1A2 0.003
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0029
6024 Cytochrome P450 1A1 CYP1A1 0.0027
6030 Cytochrome P450 2B6 CYP2B6 0.0025
6016 Cytochrome P450 2C19 CYP2C19 0.0022
5287 Signaling protein Not Available 0.0021
5288 Shikimate kinase aroK 0.0021
5304 UPF0166 protein TM_0021 TM_0021 0.0021
5270 ATP-dependent Clp protease ATP-binding subunit clpX clpX 0.0021
5314 UPF0079 ATP-binding protein HI0065 HI_0065 0.0021
5259 Transcriptional regulator ntrC1 0.0021
6699 Transcriptional regulator Cgl2612 0.0021
5290 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0021
5638 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0021
3199 Phosphopantetheine adenylyltransferase coaD 0.0021
3543 Phosphopantetheine adenylyltransferase coaD 0.0021
3567 Phosphopantetheine adenylyltransferase coaD 0.0021
5289 Phosphopantetheine adenylyltransferase coaD 0.0021
2874 Nitrogenase iron protein 1 nifH1 0.0021
4346 Polynucleotide kinase pseT 0.0021
5293 Shikimate kinase 2 aroL 0.0021
5292 Putative partitioning protein TT_C1605 0.0021
5281 Plasmid segregation protein parM parM 0.0021
5305 Phosphoribosylaminoimidazole carboxylase ATPase subunit purK 0.0021
5299 D-alanine--D-alanine ligase ddl 0.0021
6598 D-alanine--D-alanine ligase ddl 0.0021
5276 Chromosomal replication initiator protein dnaA dnaA 0.0021
5266 Activator of hgdC 0.0021
4794 Phosphoenolpyruvate carboxykinase [ATP] pckA 0.0021
5283 D-alanine--D-alanine ligase B ddlB 0.0021
5275 Multidrug resistance ABC transporter ATP-binding and permease protein lmrA 0.0021
5308 Preprotein translocase secA 1 subunit secA1 0.0021
5315 Chaperone protein htpG htpG 0.0021
1549 Heat shock 70 kDa protein 1 HSPA1A 0.0021
5284 Large T antigen Not Available 0.0021
3777 ATP-dependent Clp protease ATP-binding subunit clpA clpA 0.0021
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.0021
5261 Phosphoribosylformylglycinamidine synthase purL 0.0021
5277 Preprotein translocase subunit secA secA 0.0021
5291 Glycogen synthase 1 glgA1 0.0021
5264 DNA replication protein REP 0.0021
5285 Kinesin heavy chain KIF5B 0.0021
4106 Guanylate kinase GUK1 0.0016
4516 Guanylate kinase gmk 0.0016
6277 Heat shock cognate 71 kDa protein HSPA8 0.0016
3390 Aminoglycoside 3'-phosphotransferase aphA 0.0016
6029 Aminoglycoside 3'-phosphotransferase aphA1 0.0016
4837 Cag-alfa cag-alfa 0.0016
5646 Galactokinase GALK1 0.0016
5302 TrwB trwB 0.0016
4839 DNA polymerase III subunit tau dnaX 0.0016
4774 NTPase P4 Not Available 0.0016
4838 PMS1 protein homolog 2 PMS2 0.0016
5265 FtsH ftsH 0.0016
340 Apoptotic protease-activating factor 1 APAF1 0.0016
2270 Dephospho-CoA kinase coaE 0.0016
5189 Trimethylamine dehydrogenase tmd 0.0016
2284 Adenylate kinase adk 0.0016
2296 Adenylate kinase adk 0.0016
2311 Adenylate kinase adk 0.0016
2312 Adenylate kinase Not Available 0.0016
5295 2-keto-3-deoxy-gluconate kinase TT_P0036 0.0015
2751 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0015
4755 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0015
3470 Hypothetical protein MG245 homolog MPN_348 0.0015
3175 Glutamate--cysteine ligase gshA 0.0015
3426 Glutamine synthetase glnA 0.0015
3987 Glutamine synthetase GLUL 0.0015
5300 Antigen peptide transporter 1 TAP1 0.0015
2683 Mono-ADP-ribosyltransferase C3 C3 0.0015
2390 Nonsecretory ribonuclease RNASE2 0.0014
5312 Kinesin-like protein KIF1A KIF1A 0.0014
2282 Protein recA recA 0.0014
2315 Protein recA recA 0.0014
2332 Protein recA recA 0.0014
5263 Protein recA recA 0.0014
2922 Glycerol kinase glpK 0.0014
408 Riboflavin kinase RFK 0.0014
5271 Focal adhesion kinase 1 PTK2 0.0013
2615 Chemotaxis protein cheA cheA 0.0013
5278 Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 PAPSS1 0.0013
6832 Serine/threonine-protein kinase SRPK2 SRPK2 0.0013
1881 Hexokinase-1 HK1 0.0013
2371 Pantothenate kinase coaA 0.0013
3669 Ribokinase rbsK 0.0013
2950 Inositol-trisphosphate 3-kinase A ITPKA 0.0012
2892 Acetylglutamate kinase argB 0.0012
3550 Acetylglutamate kinase argB 0.0012
4366 Riboflavin kinase/FMN adenylyltransferase TM_0857 0.0012
825 Arsenical pump-driving ATPase ASNA1 0.0012
3435 Arsenical pump-driving ATPase arsA 0.0012
137 FolC bifunctional protein [Includes: Folylpolyglutamate synthase folC 0.0012
2697 Uridine-cytidine kinase 2 UCK2 0.0012
6857 [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial PDK2 0.0012
2727 S-adenosylmethionine synthetase metK 0.0012
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0011
788 Creatine kinase M-type CKM 0.0011
2817 Phosphoribosylglycinamide formyltransferase 2 purT 0.0011
6390 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 ATP2A1 0.0011
453 S-adenosylmethionine synthetase isoform type-1 MAT1A 0.0011
48 Pyridoxal kinase PDXK 0.0011
61 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
2644 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
2710 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
207 Glutathione synthetase GSS 0.001
5269 Glutathione synthetase gshB 0.001
2334 Dethiobiotin synthetase bioD 0.001
6555 Dethiobiotin synthetase bioD 0.001
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.001
2091 Endoplasmin HSP90B1 0.001
2511 MAP kinase-activated protein kinase 2 MAPKAPK2 0.001
2317 UDP-N-acetylmuramoylalanine--D-glutamate ligase murD 0.001
6395 Myosin-14 MYH14 0.0009
1422 Serine/threonine-protein kinase 6 AURKA 0.0009
504 Mast/stem cell growth factor receptor KIT 0.0009
3379 Kinesin-like protein KIF11 KIF11 0.0009
3456 Heat shock protein HSP 90-beta HSP90AB1 0.0009
3822 Actin, alpha skeletal muscle ACTA1 0.0009
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0008
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0008
5682 Ribonuclease pancreatic RNASE1 0.0008
1721 Glycogen synthase kinase-3 beta GSK3B 0.0008
1939 Heat shock protein HSP 90-alpha HSP90AA1 0.0007
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