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

General Information of Drug (ID: DR0917)
Drug Name
Lapatinib ditosylate
Synonyms
Lapatinib (GW-572016) Ditosylate; Lapatinib (ditosylate); Lapatinib Ditosylate; Tykerb Ditosylate; 388082-77-7; 4WK72K94MC; AK-47669; GW-57201; GW-572016F Ditosylate; N-(3-CHLORO-4-((3-FLUOROBENZYL)OXY)PHENYL)-6-(5-(((2-(METHYLSULFONYL)ETHYL)AMINO)METHYL)FURAN-2-YL)QUINAZOLIN-4-AMINE BIS(4-METHYLBENZENESULFONATE); N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazolin-4-amine; UNII-4WK72K94MC; bis(4-methylbenzene-1-sulfonic acid)
Indication Breast cancer [ICD11: 2C60] Approved [1]
Structure
3D MOL is unavailable 2D MOL
Pharmaceutical Properties Molecular Weight 925.5 Topological Polar Surface Area 240
Heavy Atom Count 62 Rotatable Bond Count 13
Hydrogen Bond Donor Count 4 Hydrogen Bond Acceptor Count 15
Cross-matching ID
PubChem CID
9941095
CAS Number
388082-77-7
TTD Drug ID
D08CDI
Formula
C43H42ClFN4O10S3
Canonical SMILES
CC1=CC=C(C=C1)S(=O)(=O)O.CC1=CC=C(C=C1)S(=O)(=O)O.CS(=O)(=O)CCNCC1=CC=C(O1)C2=CC3=C(C=C2)N=CN=C3NC4=CC(=C(C=C4)OCC5=CC(=CC=C5)F)Cl
InChI
1S/C29H26ClFN4O4S.2C7H8O3S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19;2*1-6-2-4-7(5-3-6)11(8,9)10/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35);2*2-5H,1H3,(H,8,9,10)
InChIKey
UWYXLGUQQFPJRI-UHFFFAOYSA-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
GW42393 DM000219 N. A. Unclear 1 [5]
GW690006 DM000220 N. A. Unclear 1 [5]
N-dealkylated lapatinib DM000215
21952026
Oxidation - N-Dealkylation 1 [5]
N-hydroxy lapatinib DM000218 N. A. Oxidation - N-Hydroxylation 1 [5]
O-dealkylated lapatinib DM000212
71315271
Oxidation - Debenzylation 1 [2] , [6] , [2]
O-dealkylated lapatinib DM000212
71315271
Oxidation - O-Dealkylation 1 [5]
AG2000 Free Base DM020054
163862
Oxidation - Oxidation 2 [2] , [6] , [2]
Fludarabine DM020055
657237
Conjugation - Sulfation 2 [2] , [6] , [2]
Lapatinib ditosylate metabolite M1-glucuronide conjugate DM000223 N. A. Conjugation - Glucuronidation 2 [2] , [6] , [2]
Nitroso intermediate DM000216 N. A. Unclear 2 [5]
Reactive Quinoneimine metabolite DM000213
118753021
Unclear 2 [2] , [6] , [2]
Reactive Quinoneimine metabolite DM000213
118753021
Unclear 2 [5]
Glutathione adducts DM000214 N. A. Unclear 3 [5]
Lapatinib ditosylate metabolite M2 DM000217 N. A. Unclear 3 [5]
Quinoneimine-GSH conjugate DM000222 N. A. Conjugation - Conjugation 3 [2]
⏷ Show the Full List of 15  DM(s)
The Full List of Metabolic Reaction (MR) of This Drug
MR ID Reactant Product MR Type DME REF
MR001427 Lapatinib ditosylate O-dealkylated lapatinib Oxidation - O-Dealkylation CYP3A4 ... [5]
MR001428 Lapatinib ditosylate N-dealkylated lapatinib Oxidation - N-Dealkylation CYP3A4 ... [5]
MR001429 Lapatinib ditosylate N-hydroxy lapatinib Oxidation - N-Hydroxylation CYP3A4 ... [5]
MR001430 Lapatinib ditosylate GW42393 Unclear Unclear [5]
MR001431 Lapatinib ditosylate GW690006 Unclear Unclear [5]
MR001424 Lapatinib ditosylate metabolite M1 Lapatinib ditosylate metabolite M1-glucuronide conjugate Conjugation - Glucuronidation UGT [2], [6], [2]
MR001425 Lapatinib ditosylate metabolite M1 Lapatinib ditosylate metabolite M1-sulfate conjugate Conjugation - Sulfation SULT [2], [6], [2]
MR001426 Lapatinib ditosylate metabolite M1 Lapatinib ditosylate metabolite M3 Oxidation - Oxidation AOX1 [2], [6], [2]
MR001421 N-dealkylated lapatinib Nitroso intermediate Unclear Unclear [5]
MR001423 N-hydroxy lapatinib Nitroso intermediate Unclear Unclear [5]
MR001418 O-dealkylated lapatinib Reactive Quinoneimine metabolite Unclear Unclear [5]
MR001422 Nitroso intermediate Lapatinib ditosylate metabolite M2 Unclear Unclear [5]
MR001419 Reactive Quinoneimine metabolite Glutathione adducts Unclear Unclear [5]
MR001420 Reactive Quinoneimine metabolite Quinoneimine-GSH conjugate Conjugation - Conjugation GCLC [2]
⏷ Show the Full List of 14 MR(s)
Drug-Metabolizing Enzyme(s) (DME) Metabolizing This Drug
DME Name DME Info Species Uniprot ID EC Number REF
Aldehyde oxidase (AOX1) DME0052 Homo sapiens
AOXA_HUMAN
1.2.3.1
[2]
Cytochrome P450 1A2 (CYP1A2) DME0003 Homo sapiens
CP1A2_HUMAN
1.14.14.1
[3]
Cytochrome P450 2C8 (CYP2C8) DME0018 Homo sapiens
CP2C8_HUMAN
1.14.14.1
[4]
Cytochrome P450 2C9 (CYP2C9) DME0019 Homo sapiens
CP2C9_HUMAN
1.14.14.1
[3]
Cytochrome P450 2D6 (CYP2D6) DME0009 Homo sapiens
CP2D6_HUMAN
1.14.14.1
[3]
Cytochrome P450 3A4 (CYP3A4) DME0001 Homo sapiens
CP3A4_HUMAN
1.14.14.55
[4]
Cytochrome P450 3A5 (CYP3A5) DME0012 Homo sapiens
CP3A5_HUMAN
1.14.14.1
[3]
Glutamate-cysteine ligase catalytic (GCLC) DME0485 Homo sapiens
GSH1_HUMAN
6.3.2.2
[2]
Mephenytoin 4-hydroxylase (CYP2C19) DME0021 Homo sapiens
CP2CJ_HUMAN
1.14.14.1
[3]
Sulfotransferase (SULT) DMEN061 . Not Available Not Available [2]
⏷ Show the Full List of 10  DME(s)
References
1 Lapatinib Ditosylate was approved by FDA. The 2020 official website of the U.S. Food and Drug Administration.
2 Detoxication versus Bioactivation Pathways of Lapatinib In Vitro: UGT1A1 Catalyzes the Hepatic Glucuronidation of Debenzylated Lapatinib Drug Metab Dispos. 2021 Mar;49(3):233-244. doi: 10.1124/dmd.120.000236.
3 Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
4 Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703.
5 Metabolic intermediate complex formation of human cytochrome P450 3A4 by lapatinib Drug Metab Dispos. 2011 Jun;39(6):1022-30. doi: 10.1124/dmd.110.037531.
6 Case Study 11: Considerations for Enzyme Mapping Experiments-Interaction Between the Aldehyde Oxidase Inhibitor Hydralazine and Glutathione. Methods Mol Biol. 2021;2342:809-823. doi: 10.1007/978-1-0716-1554-6_30.

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