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

General Information of Drug (ID: DR0921)
Drug Name
Leflunomide
Prodrug Info Leflunomide is the prodrug of A77 1726
Synonyms
Leflunomida; Leflunomida [INN-Spanish]; Leflunomidum; Leflunomidum [INN-Latin]; Lefunomide [Inn-Spanish]; SU 101 (pharmaceutical); SU-101; leflunomide; lefunamide; 5-Methyl-N-(4-(trifluoromethyl)phenyl)-4-isoxazolecarboxamide; Arava (TN); 5-Methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide; 5-methyl-N-(4-(trifluoromethyl)phenyl)isoxazole-4-carboxamide; 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide; 75706-12-6; Arava; HWA 486; HWA-486; SU101; UNII-G162GK9U4W
Indication Rheumatoid arthritis [ICD11: FA20] Approved [1]
Structure
3D MOL 2D MOL
Pharmaceutical Properties Molecular Weight 270.21 Topological Polar Surface Area 55.1
Heavy Atom Count 19 Rotatable Bond Count 2
Hydrogen Bond Donor Count 1 Hydrogen Bond Acceptor Count 6
Cross-matching ID
PubChem CID
3899
PubChem SID
10107 ; 517091 ; 604245 ; 855764 ; 866530 ; 6899003 ; 7847814 ; 7979735 ; 8150074 ; 8152456 ; 10321188 ; 11111382 ; 11111383 ; 11336091 ; 11361330 ; 11363216 ; 11365778 ; 11368340 ; 11376502 ; 11462302 ; 11466800 ; 11467920 ; 11486519 ; 11494136 ; 11528672 ; 11533365 ; 12013774 ; 15221872 ; 17405210 ; 24278516 ; 26612550 ; 26746985 ; 26746986 ; 26746987 ; 29223013 ; 46506013 ; 47589061 ; 47662351 ; 47736556 ; 47885478 ; 48110514 ; 48259307 ; 48259308 ; 48416160 ; 49698814 ; 49835013 ; 50100264 ; 50104054 ; 50104055 ; 50104056
ChEBI ID
ChEBI:6402
CAS Number
75706-12-6
TTD Drug ID
D08ROP
Formula
C12H9F3N2O2
Canonical SMILES
CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F
InChI
1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
InChIKey
VHOGYURTWQBHIL-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
5-Methylisoxazole carboxylic acid DM000229
76947
Oxidation - Deamination 1 [6]
A77 1726 DM000226
54684141
Oxidation - N-Dealkylation 1 [6] , [5]
Trifluoromethylaniline DM000228
12699875
Oxidation - Deamination 1 [6]
Unclear DM009999 N. A. Unclear 1 [3]
Unclear DM009999 N. A. Unclear 1 [4]
Leflunomide metabolite M1 DM000227
23500906
Unclear 2 [7]
The Full List of Metabolic Reaction (MR) of This Drug
MR ID Reactant Product MR Type DME REF
MR003102 Leflunomide A77 1726 Oxidation - N-Dealkylation CYP1A2 [6], [5]
MR003103 Leflunomide Trifluoromethylaniline Oxidation - Deamination Unclear [6]
MR003104 Leflunomide 5-Methylisoxazole carboxylic acid Oxidation - Deamination Unclear [6]
MR003105 Leflunomide . Unclear CYP2C9 [3]
MR003101 A77 1726 Leflunomide metabolite M1 Unclear Unclear [7]
Drug-Metabolizing Enzyme(s) (DME) Metabolizing This Drug
DME Name DME Info Species Uniprot ID EC Number REF
Cytochrome P450 1A2 (CYP1A2) DME0003 Homo sapiens
CP1A2_HUMAN
1.14.14.1
[2]
Cytochrome P450 2C9 (CYP2C9) DME0019 Homo sapiens
CP2C9_HUMAN
1.14.14.1
[3]
Cytochrome P450 3A4 (CYP3A4) DME0001 Homo sapiens
CP3A4_HUMAN
1.14.14.55
[4]
Cytochrome P450 3A4 (CYP3A4) DME0001 Homo sapiens
CP3A4_HUMAN
1.14.14.55
[5]
Mephenytoin 4-hydroxylase (CYP2C19) DME0021 Homo sapiens
CP2CJ_HUMAN
1.14.14.1
[5]
References
1 Leflunomide was approved by FDA. The 2020 official website of the U.S. Food and Drug Administration.
2 Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
3 Leflunomide-induced acute hepatitis. Dig Liver Dis. 2004 Jan;36(1):82-4.
4 Prediction of drug-induced liver injury in HepG2 cells cultured with human liver microsomes. Chem Res Toxicol. 2015 May 18;28(5):872-85.
5 In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes Drug Metab Dispos. 2003 Oct;31(10):1240-50. doi: 10.1124/dmd.31.10.1240.
6 In vitro metabolism of leflunomide by mouse and human liver microsomes Drug Metab Lett. 2007 Dec;1(4):299-305. doi: 10.2174/187231207783221402.
7 A redox-mediated Kemp eliminase Nat Commun. 2017 Mar 28;8:14876. doi: 10.1038/ncomms14876.

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