Details of the Drug Metabolized by Drug-Metabolizing Enzyme (DME)

General Information of Drug (ID: DR0765)
Drug Name
Gemcitabine
Synonyms
Gamcitabine; Gemcitabina; Gemcitabina [INN-Spanish]; Gemcitabine HCl; Gemcitabinum; Gemcitabinum [INN-Latin]; LY-188011; LY188011; Cytidine, 2'-deoxy-2',2'-difluoro-; DFdCyd; GEMCITABINE HYDROCHLORIDE; SDUQYLNIPVEERB-QPPQHZFASA-N; gemcitabine; 122111-03-9; 2',2'-Difluorodeoxycytidine; 2',2'-difluoro-2'-deoxycytidine; 2'-Deoxy-2',2'-difluorocytidine; 4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one; 95058-81-4; B76N6SBZ8R; CHEBI:175901; DDFC; NSC 613327; UNII-B76N6SBZ8R; dFdC
Indication Breast cancer [ICD11: 2C60] Approved [1]
Structure
3D MOL 2D MOL
Pharmaceutical Properties Molecular Weight 263.2 Topological Polar Surface Area 108
Heavy Atom Count 18 Rotatable Bond Count 2
Hydrogen Bond Donor Count 3 Hydrogen Bond Acceptor Count 6
Cross-matching ID
PubChem CID
60750
PubChem SID
9852 ; 597200 ; 829253 ; 7849427 ; 7887820 ; 7979381 ; 8187035 ; 15197115 ; 15221618 ; 24769903 ; 24875076 ; 43118104 ; 46506425 ; 49684285 ; 49835789 ; 49960194 ; 50298729 ; 53787881 ; 56311575 ; 56312523 ; 56312627 ; 56312648 ; 56313191 ; 56313205 ; 56313872 ; 57304498 ; 57314089 ; 60815357 ; 87322653 ; 92308986 ; 103233471 ; 104321551 ; 117682518 ; 121264498 ; 124893555 ; 127340623 ; 127340624 ; 129221764 ; 134338484 ; 135022769 ; 135684653 ; 136367931 ; 136369166 ; 137001852 ; 142312486 ; 143493338 ; 144116012 ; 152059722 ; 152240379 ; 152258737
ChEBI ID
CHEBI:175901
CAS Number
95058-81-4
TTD Drug ID
D03UVS
Formula
C9H11F2N3O4
Canonical SMILES
C1=CN(C(=O)N=C1N)C2C(C(C(O2)CO)O)(F)F
InChI
1S/C9H11F2N3O4/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17)/t4-,6-,7-/m1/s1
InChIKey
SDUQYLNIPVEERB-QPPQHZFASA-N
The Metabolic Roadmap of This Drug
The Full List of Drug Metabolites (DM) of This Drug
DM Name DM ID PubChem ID Reaction DM Level REF
2',2'-Difluorodeoxyuridine DM002092
9871558
Oxidation - Deamination 1 [7] , [9]
DFdCMP DM002088
503015
Other reaction - Phosphorylation 1 [7] , [9]
2',2'-difluorodeoxyuridine monophosphate DM002091
44448712
Oxidation - Deamination 2 [5]
DFdCDP DM002089
6420157
Other reaction - Phosphorylation 2 [6]
DFdCTP DM002090
130659
Other reaction - Phosphorylation 3 [6] , [10] , [11]
The Full List of Metabolic Reaction (MR) of This Drug
MR ID Reactant Product MR Type DME REF
MR001121 Gemcitabine Gemcitabine Monophosphate Other reaction - Phosphorylation DCK ... [7], [9]
MR001122 Gemcitabine 2',2'-Difluorodeoxyuridine Oxidation - Deamination cdd [7], [9]
MR001118 Gemcitabine Monophosphate Gemcitabine diphosphate Other reaction - Phosphorylation CMPK1 [6]
MR001119 Gemcitabine Monophosphate 2',2'-difluorodeoxyuridine monophosphate Oxidation - Deamination DCTD [5]
MR001120 Gemcitabine diphosphate Gemcitabine triphosphate Other reaction - Phosphorylation ndk [6], [10], [11]
Drug-Metabolizing Enzyme(s) (DME) Metabolizing This Drug
DME Name DME Info Species Uniprot ID EC Number REF
Cytidine aminohydrolase (CDA) DME0080 Homo sapiens
CDD_HUMAN
3.5.4.5
[2]
Cytidine deaminase (cdd) DME1055 Escherichia coli
CDD_ECOLI
3.5.4.5
[3]
Cytidine deaminase (cdd) DME1056 Klebsiella pneumoniae
CDD_KLEP7
3.5.4.5
[3]
Cytidine deaminase (cdd) DME1196 Mycoplasma hyorhinis
E0TLJ6_MYCHH
3.5.4.5
[4]
Deoxycytidylate deaminase (DCTD) DME0112 Homo sapiens
DCTD_HUMAN
3.5.4.12
[5]
Nucleoside diphosphate kinase (ndk) DMEN041 Escherichia coli
NDK_ECOLI
4.2.1.77
[6]
Thymidine kinase 2 (TK2) DMEN045 Homo sapiens
KITM_HUMAN
Not Available [7]
Uridine/cytidine monophosphate kinase (UMPK) DME0456 Homo sapiens
KCY_HUMAN
2.7.4.14
[8]
⏷ Show the Full List of 8  DME(s)
Experimental Enzyme Kinetic Data of This Drug
DME Name DME Info Kinetic Data Uniprot ID REF
Cytidine deaminase (cdd) DME1196 Km = 2586 microM
E0TLJ6_MYCHH
[4]
Uridine/cytidine monophosphate kinase (UMPK) DME0456 Km = 0.0146 microM
KCY_HUMAN
[8]
References
1 Gemcitabine was approved by FDA. The 2020 official website of the U.S. Food and Drug Administration.
2 Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours. Br J Clin Pharmacol. 2011 Mar;71(3):437-44.
3 Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017 Sep 15;357(6356):1156-1160.
4 Mycoplasma hyorhinis-encoded cytidine deaminase efficiently inactivates cytosine-based anticancer drugs. FEBS Open Bio. 2015 Aug 3;5:634-9.
5 LC-MS/MS method for quantitation of gemcitabine and its metabolite 2',2'-difluoro-2'-deoxyuridine in mouse plasma and brain tissue: Application to a preclinical pharmacokinetic study J Pharm Biomed Anal. 2021 May 10;198:114025. doi: 10.1016/j.jpba.2021.114025.
6 Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2',2'-difluorodeoxyuridine and their nucleotides Br J Clin Pharmacol. 2018 Jun;84(6):1279-1289. doi: 10.1111/bcp.13557.
7 Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective Cancer Chemother Pharmacol. 2016 Jul;78(1):1-12. doi: 10.1007/s00280-016-3003-0.
8 Gemcitabine pharmacogenomics: deoxycytidine kinase and cytidylate kinase gene resequencing and functional genomics. Drug Metab Dispos. 2008 Sep;36(9):1951-9.
9 Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer Drugs. 1997 Sep;54(3):447-72. doi: 10.2165/00003495-199754030-00009.
10 A metal-dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine-5'-triphosphate. Protein Sci. 2023 Jun;32(6):e4648. doi: 10.1002/pro.4648.
11 Microangiopathy associated with gemcitabine: a drug interaction with nab-paclitaxel? A case series and literature review. Eur J Clin Pharmacol. 2022 Jul;78(7):1087-1093. doi: 10.1007/s00228-022-03324-z.

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