title: Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation.
abstract: BACKGROUND
  Patients with diabetes have increased rates of cardiovascular events, and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. This study was undertaken to investigate the interaction potential between sulfonylurea drugs and clopidogrel, with an emphasis on key steps in the clopidogrel bioactivation processes.
  
  
  METHODS
  Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in human liver microsomes (HLM), human intestinal microsomes and recombinant human enzymes. CYP2C9-based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using HLM and the recombinant CYP2C9 system.
  
  
  RESULTS
  For the formation of clopidogrel carboxylic acid (the deactivation step) and 2-oxo-clopidogrel (the first step of bioactivation) in human microsomes, the inhibition potency of the 3 sulfonylurea drugs tested followed the order of glimepiride > glipizide > gliclazide. For the metabolism of 2-oxo-clopidogrel (the second step of bioactivation), glimepiride demonstrated a relatively strong inhibition against CYP2C9 activity (IC50 12.7 μmol/l). In addition, 2-oxo-clopidogrel displayed a moderate inhibitory effect toward the CYP2C9-mediated metabolism of glimepiride.
  
  
  CONCLUSIONS
  The moderate inhibition observed for clopidogrel bioactivation may not present a significant risk for drug-drug interactions between sulfonylureas and clopidogrel. While these findings bode well for multidrug therapies involving sulfonylureas and clopidogrel, clinical investigations are needed to define the clinical risk and benefit for combining these agents for the management of cardiovascular events in diabetic patients.
authors.affiliation: Department of Pharmacy, Zhongda Hospital, Southeast University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Shao
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: Yun-Ting
authors.initials: YT
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhan
authors.forename: Guo-Ming
authors.initials: GM
authors.lastname: Chen
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhang
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D000077144:Clopidogrel; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005907:Gliclazide / Q000494:pharmacology; D005913:Glipizide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000473:pathology; D008861:Microsomes / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D065688:Cytochrome P-450 CYP2C9 Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C528640:clopidogrel carboxylic acid; C540904:2-oxo-clopidogrel; C057619:glimepiride; D000077144:Clopidogrel; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D005907:Gliclazide; D013988:Ticlopidine; D005913:Glipizide