Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDILSGBR67)
  Drug Name Clopidogrel Drug Info Pioglitazone Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiplatelet Agents Antidiabetic Agents
  Structure

 Mechanism of Clopidogrel-Pioglitazone Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Clopidogrel Pioglitazone
      Mechanism CYP450 2C8 inhibitor CYP450 2C8 substrate
      Key Mechanism Factor 1
Factor Name Cytochrome P450 2C8
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Structure Sequence
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV
Gene Name CYP2C8
Uniprot ID CP2C8_HUMAN
KEGG Pathway hsa:1558
Protein Family Cytochrome P450 family
Protein Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
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      Mechanism Description
  • Decreased metabolism of Pioglitazone caused by Clopidogrel mediated inhibition of CYP450 enzyme

Recommended Action
      Management Given the potential for dose-related adverse events, reduction of pioglitazone dosage should be considered when used with clopidogrel. Close monitoring for the development of hypoglycemia and other adverse effects is recommended, such as fluid retention weight gain new or worsening heart failure pulmonary, peripheral, and macular edema bone fractures anemia and liver enzyme elevations. Patients should regularly monitor their blood sugar and learn how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitation. Likewise, patients should be observed for potential loss of glycemic control following discontinuation of clopidogrel, and the pioglitazone dosage adjusted as necessary.

References
1 Itkonen MK, Tornio A, Neuvonen M, Neuvonen PJ, Niemi M, Backman JT "Clopidogrel Markedly Increases the Plasma Concentrations of the CYP2C8 Substrate Pioglitazone." Drug Metab Dispos (2016):. [PMID: 27260150]
2 Product Information. Actos (pioglitazone) Takeda Pharmaceuticals America, Lincolnshire, IL.
3 Product Information. Plavix (clopidogrel). Bristol-Myers Squibb, Princeton, NJ.
4 Tornio A, Filppula A, Kailari O, et al. "Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as perpetrator of drug-drug interactions." Clin Pharmacol Ther 96 (2014): 498-507. [PMID: 24971633]