Drug Information

Drug (ID: DG00549) and It's Reported Resistant Information

• Name: Clopidogrel
• Synonyms: Clopidogrel; 113665-84-2; Plavix; (S)-Clopidogrel; Zyllt; Clopidogrel bisulfate; Clopidogrel Acino; Clopidogrel Hexal; (+)-Clopidogrel; CLOPIDOGREL SULFATE; (+)-(S)-Clopidogrel; UNII-A74586SNO7; Clopidogrel BMS; SR 25990; methyl (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate; CHEBI:37941; SR-25990C; A74586SNO7; Isocover; R 130964; (S)-Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate; Clopidogrel (TN); Plavix (TN); methyl (2S)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanoate; Thrombo; Clopidogrel [INN:BAN]; clopidogrel Sandoz; CHEMBL1083385; methyl (2S)-2-(2-chlorophenyl)-2-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl}acetate; SMR000550475; Clopidogrel Winthrop; Clopidogrel 1A Pharma; HSDB 7430; NSC-758613; Clopidogrel ratiopharm GmbH; Plavix® Clopidogrel apotex; (+) clopidogrel; CGE; Clopidogrel Teva (hydrogen sulphate); Clopidogrel-ratiopharm; Clopidogrel 1a-pharma; Spectrum_000105; CPD000550475; Clopidogrel (USP/INN); Spectrum2_000512; Spectrum3_001606; Spectrum4_000175; SCHEMBL4769; THIAMINELAURYLSULPHATE; CHEMBL1771; methyl (2S)-(2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate; BSPBio_003211; KBioGR_000689; KBioSS_000545; MLS001165708; MLS001195633; MLS001304711; MLS006011891; BIDD:GT0284; DivK1c_000787; SPBio_000463; GTPL7150; DTXSID6022848; HMS502H09; KBio1_000787; KBio2_000545; KBio2_003113; KBio2_005681; KBio3_002431; AMY8913; NINDS_000787; HMS2090O21; HMS2234N16; HMS3259B08; HMS3715J08; BBL010770; BDBM50318910; BDBM50397662; MFCD05662337; NSC748298; STK580572; ZINC34781704; AKOS005504280; CCG-221243; CS-0656; DB00758; MCULE-9061369538; NC00703; NSC 758613; NSC-748298; IDI1_000787; Methyl (+)-(S)-alpha-(o-chlorophenyl)-6,7-dihydrothieno(3,2-c)pyridine-5(4H)-acetate; NCGC00163329-02; NCGC00163329-04; AC-19024; DS-13362; HY-15283; Thieno(3,2-c)pyridine-5(4H)-acetic acid, alpha-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (S)-; SBI-0052755.P002; D07729; N11780; AB00053786-07; AB00053786-08; AB00053786_09; AB00053786_10; Q410237; R-130964; BRD-K27721098-065-02-9; BRD-K27721098-065-05-2; UNII-MX75HY8K68 component GKTWGGQPFAXNFI-HNNXBMFYSA-N; methyl (2-chlorophenyl)(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate; (S)-(+)-Methyl (2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate; (S)-(+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate; methyl (+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate; methyl (+)-(s)-alpha-(o-chlorophenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4h)-acetate; methyl (S)-(+)-alpha-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate; methyl(+)-(s)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4h) acetate; methyl-(S)-(+)-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)-acetate; (+)-(S)-(2-Chlorophenyl) (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester; (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid methyl ester; Thieno[3,2-c]pyridine-5(4H)-acetic acid, .alpha.-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (.alpha.S)-; Thieno[3,2-c]pyridine-5(4H)-acetic acid, alpha-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (alphaS)-
• Indication:
  In total 1 Indication(s)
  Thrombosis [ICD-11: DB61-GB90]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  Cerebral ischaemic stroke [ICD-11: 8B11]; [2]
  Coronary artery disease [ICD-11: BA8Z]; [3]
  Heart failure [ICD-11: BD10]; [4]
  Myocardial infarction [ICD-11: BA41]; [1]
  Peripheral arterial disease [ICD-11: BD4Z]; [5]
• Target: P2Y purinoceptor 12 (P2RY12); P2Y12_HUMAN; [4]
• Formula: C16H16ClNO2S
• IsoSMILES: COC(=O)[C@H](C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3
• InChI: 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
• InChIKey: GKTWGGQPFAXNFI-HNNXBMFYSA-N
• PubChem CID: 60606
• ChEBI ID: CHEBI:37941
• TTD Drug ID: D0N0TZ
• VARIDT ID: DR00245
• DrugBank ID: DB00758

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-08: Nervous system diseases

Cerebral ischaemic stroke [ICD-11: 8B11]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 1 subfamily A member 1 (CYP1A1) [6]

• Molecule Alteration: Missense mutation; CYP3A5 (rs776746) GG + AG and CYP2C19*2 (rs4244285) AA + AG genotypes
• Resistant Disease: Acute Ischemic Stroke [ICD-11: 8B11.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Matrix-assisted laser desorption/ionization time of flight mass spectrometry assay
• Experiment for Drug Resistance: Platelet aggregation test assay
• Mechanism Description: The estimated risk of clopidogrel resistance was significantly higher in patients with CYP3A5 (rs776746) GG and CYP2C19*2 (rs4244285) AA, as compared to patients harboring CYP3A5 (rs776746) AA and CYP2C19*2 (rs4244285) GG. These data suggest that these two CYP genetic variants together significantly contributed to clopidogrel resistance. The relative risk conferred by the combinations of CYP3A5 GG and CYP2C19*2 AA was considered as a high-risk variable, with assigned as one, and other combinations of CYP3A5 and CYP2C19*2 as a low-risk variable, with assigned as zero.

ICD-11: Circulatory system diseases

Myocardial infarction [ICD-11: BA41]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) [1]

• Molecule Alteration: SNP; CYP2C19*2+CYP2C19*3
• Resistant Disease: Acute myocardial infarction [ICD-11: BA41.1]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We defined CYP2C19*2 and CYP2C19*3 as CYP2C19 loss-of-function alleles (LoFA), indicating possible clopidogrel resistance.

Coronary artery disease [ICD-11: BA8Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) [3]

• Molecule Alteration: SNP; CYP2C19*2
• Resistant Disease: Coronary artery disease [ICD-11: BA8Z.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood sample; N.A.
• Experiment for Molecule Alteration: Genetic analysis assay
• Experiment for Drug Resistance: Platelet aggregation test assay
• Mechanism Description: Among the 72 patients studied, 32.6% were carriers of CYP2C19*2 loss-of-function allele. This allele was found to be more common but not significantly so from the controls (27.7%). The loss-of-function genotypes (*2/*2 or *2/*1) of CYP2C19 were seen to be significantly higher in clopidogrel semi-responders compared to responders (72.9% vs 34.3%, P = 0.0023, respectively). Similarly, significantly higher frequency of the mutant *2 allele of CYP2C19 was observed in clopidogrel semi-responders than in responders (43.2% vs 21.4%, P = 0.007).

Heart failure [ICD-11: BD10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: P2Y purinoceptor 1 (P2RY1) [4]

• Molecule Alteration: SNP; rs701265+rs1439010+rs1371097+rs1065776+rs12497578
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Purinergic receptor P2Y12 (P2RY12) [4]

• Molecule Alteration: SNP; rs2046934+rs12637988+rs16863336+rs6798347+rs16863323+rs9859538+rs16846673+rs6809699+rs6785930+rs5853517+rs10935838
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Liver carboxylesterase 1 (CES1) [4]

• Molecule Alteration: SNP; rs8192950
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) [4]

• Molecule Alteration: SNP; rs4244285+rs4986893+rs28399504+rs56337013+rs72552267+rs72558186+rs12248560
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 2 subfamily C member 9 (CYP2C9) [4]

• Molecule Alteration: SNP; rs1799853+rs1057910
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [4]

• Molecule Alteration: SNP; rs2740574+rs55785340+rs4986910
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Cytochrome P450 family 3 subfamily A member 5 (CYP3A5) [4]

• Molecule Alteration: SNP; rs776746
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Key Molecule: Paraoxonase 1 (PON1) [4]

• Molecule Alteration: SNP; rs662
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Molecule Alteration: SNP; rs1045642+rs2032562
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Integrin subunit beta 3 (ITGB3) [4]

• Molecule Alteration: SNP; rs5918
• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Peripheral arterial disease [ICD-11: BD4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) [5]

• Molecule Alteration: SNP; .
• Resistant Disease: Peripheral arterial disease [ICD-11: BD4Z.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Whole blood; N.A.
• Experiment for Drug Resistance: VerifyNow P2Y12 assay
• Mechanism Description: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form.CYP 2C19 genetic polymorphism may result clopidogrel resistance.

References

• Ref 1: Assessment of Risk Factors for Drug Resistance of Dual Anti Platelet Therapy After PCI .Clin Appl Thromb Hemost. 2022 Jan-Dec;28:10760296221083674. doi: 10.1177/10760296221083674. 10.1177/10760296221083674
• Ref 2: Antiplatelet drug resistance is associated with early neurological deterioration in acute minor ischemic stroke in the Chinese population .J Neurol. 2016 Aug;263(8):1612-9. doi: 10.1007/s00415-016-8181-5. Epub 2016 Jun 3. 10.1007/s00415-016-8181-5
• Ref 3: Association of CYP2C19, CYP3A5 and GPIIb/IIIa gene polymorphisms with Aspirin and Clopidogrel Resistance in a cohort of Indian patients with Coronary Artery Disease .Int J Lab Hematol. 2015 Dec;37(6):809-18. doi: 10.1111/ijlh.12416. Epub 2015 Aug 12. 10.1111/ijlh.12416
• Ref 4: Gene polymorphisms in dual antiplatelet therapy and the presence of hypo-attenuated leaflet thickening after transcatheter aortic valve replacement .J Thromb Thrombolysis. 2018 Apr;45(3):463-465. doi: 10.1007/s11239-018-1636-z. 10.1007/s11239-018-1636-z
• Ref 5: CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia .Eur J Vasc Endovasc Surg. 2019 Sep;58(3):373-382. doi: 10.1016/j.ejvs.2019.02.011. Epub 2019 Aug 5. 10.1016/j.ejvs.2019.02.011
• Ref 6: Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke .J Atheroscler Thromb. 2016 Oct 1;23(10):1188-1200. doi: 10.5551/jat.33290. Epub 2016 Mar 8. 10.5551/jat.33290