Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies

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• 作者：Alok Shiomurti Tripathi ; Ajay Kumar Timiri…
• 关键词：Diabetic nephropathy ; Glimepiride ; Sildenafil citrate ; Pharmacokinetics ; Homology modeling ; Schrodinger
• 刊名：Journal of Molecular Modeling
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：21
• 期：10
• 全文大小：2,052 KB
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• 作者单位：Alok Shiomurti Tripathi (1) (2)
  Ajay Kumar Timiri (2)
  Papiya Mitra Mazumder (2)
  Anil Chandewar (3)
  
  1. Department of Pharmacology, P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija Nagar, Yavatmal, MS, 445001, India
  2. Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India, 835215
  3. Department of Pharmaceutical Chemistry, P. Wadhwani College of Pharmacy, Yavatmal, Maharashtra, India, 445001
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

The present study evaluates possible drug interactions between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ)-induced diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction based on molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg kg?, i.p.) and was confirmed by assessing blood and urine biochemical parameters 28 days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5 mg kg?, p.o.) and SIL (2.5 mg kg?, p.o.) on the 29th and 70th day of the protocol. Possible drug interaction was assessed by evaluating the plasma drug concentration using HPLC-UV and changes in biochemical parameters in blood and urine were also determined. The mechanism of the interaction was postulated from the results of a molecular modeling study using the Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in blood and urine biochemical parameters in STZ-treated groups. The concentration of SIL increased significantly (P-lt;-.001) in rat plasma when co-administered with GLIM on the 70th day of the protocol. Molecular modeling revealed important interactions with rat serum albumin and CYP2C9. GLIM has a strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL, whereas for CYP2C9, GLIM forms a stronger hydrogen bond than SIL with polar contacts and hydrophobic interactions. The present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals, and the mechanism is supported by molecular modeling studies. Keywords Diabetic nephropathy Glimepiride Sildenafil citrate Pharmacokinetics Homology modeling Schrodinger