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

• Published in: Journal of molecular modeling Vol. 21; no. 10; p. 276
• Main Authors: Tripathi, Alok Shiomurti, Timiri, Ajay Kumar, Mazumder, Papiya Mitra, Chandewar, Anil
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2015
• Subjects: Animals; Blood Glucose; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Cytochrome P-450 CYP2C9 - chemistry; Cytochrome P-450 CYP2C9 - metabolism; Diabetic Nephropathies - blood; Diabetic Nephropathies - drug therapy; Disease Models, Animal; Drug Interactions; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Kidney Function Tests; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Medicine; Molecular Structure; Original Paper; Phosphodiesterase 5 Inhibitors - chemistry; Phosphodiesterase 5 Inhibitors - pharmacokinetics; Protein Conformation; Rats; Serum Albumin - chemistry; Serum Albumin - metabolism; Sildenafil Citrate - chemistry; Sildenafil Citrate - pharmacokinetics; Structure-Activity Relationship; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacokinetics; Theoretical and Computational Chemistry; Sildenafil citrate; Glimepiride; Diabetic nephropathy; Schrodinger; Pharmacokinetics; Homology modeling
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-015-2823-x

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 −1 , 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 −1 , p.o.) and SIL (2.5 mg kg −1 , 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  < 0.001) 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.