Interaction Potential Between Clopidogrel And Sulfonylurea Antidiabetic Agents

Aim: Clopidogrel is a prodrug that is commonly used for cardiovascular diseases. The drug is metabolized by a series of enzymes. Patients with diabetes have increased rates of cardiovascular events and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. Sulfonylureas are oral antidiabetic agents which are mainly metabolized by CYP2 C enzymes. Since CYP2 C enzymes are also involved in clopidogrel metabolism, drug-drug interaction may occur when they are administered together. The present study was designed to investigate the interaction potential between sulfonylurea drugs and clopidogrel both in vitro and in vivo.Methods: Liquid chromatography-tandem mass spectrometry(LC-MS/MS) methods were developed for sulfonylureas, clopidogrel and its metabolites. Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in liver microsomes, intestinal microsomes and recombinant enzymes. CYP2C9 based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using the recombinant CYP2C9 system. Stably transfected cell lines were used to investigate uptake and efflux mechanisms as well as the interaction potential between clopidogrel and glimepiride. In vivo pharmacokinetic and DDI studies were carried out in SD rats.Results: In human liver microsomes, the formation of clopidogrel carboxylic acid was more predominant than that of 2-oxo-clopidogrel and yet the reverse order was found in human intestinal microsomes, suggesting tissue specificity. Among the three sulfonylurea drugs tested, glimepiride showed a weak inhibition toward CES1 and a moderate inhibition against CYP2C9 activity(IC50 = 12.7 ?M). On the other hand, 2-oxo-clopidogrel displayed a moderate inhibitory effect against CYP2C9. Studies based on transporters indicated that glimepiride were the substrates of both MDR1 and BCRP and clopidogrel could inhibit MDR1 and BCRP mediated glimepiride efflux transport. In vivo DDI showed that the Cmax and AUC0-t was lower in the combination therapy. The Cmax of clopidogrel carboxylic acid, 2-oxo-clopidogrel, clopidogrel and glimepiride decreased about 34.0%, 53.6%, 72.8% and 12.3%, respectively, while the AUC0-t of these four drugs decreased about 33.8%, 44.9%, 46.5% and 24.0%, respectively.Conclusion: In the present study, DDIs between clopidogrel and glimepiride were investigated both in vitro and in vivo. The results showed that clopidogrel used in combination with sulfonylureas could lead to moderate drug-drug interactions. Experiments in HLM, HIM and recombinant enzymes indicated that inhibition could occur at each step in the metabolism. In addition, studies on transporters revealed that glimepiride was the substrate of both MDR1 and BCRP and clopidogrel could inhibit both MDR1 and BCRP mediated glimepiride efflux transport. Based on PK results in SD rats, clopidogrel and glimepiride administered together led to reductions in drug exposure. Taken together, futher studies in the clinical setting are needed to verify the potential interactions which could lead to safe and effective use of the above drug combinations in treating diabetic patients with cardiovascular events.