title: Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies.
abstract: 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.
authors.affiliation: Department of Pharmacology, P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija Nagar, Yavatmal, MS, 445001, India. shloksk@gmail.com.|Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India, 835215. shloksk@gmail.com.
authors.forename: Alok Shiomurti
authors.initials: AS
authors.lastname: Tripathi
authors.affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India, 835215.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Timiri
authors.affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India, 835215.
authors.forename: Papiya Mitra
authors.initials: PM
authors.lastname: Mazumder
authors.affiliation: Department of Pharmaceutical Chemistry, P. Wadhwani College of Pharmacy, Yavatmal, Maharashtra, India, 445001.
authors.forename: Anil
authors.initials: A
authors.lastname: Chandewar
mesh_terms: D000818:Animals; D001786:Blood Glucose; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy; D004195:Disease Models, Animal; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D007677:Kidney Function Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011487:Protein Conformation; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D000068677:Sildenafil Citrate / Q000737:chemistry* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D058986:Phosphodiesterase 5 Inhibitors; D012709:Serum Albumin; D013453:Sulfonylurea Compounds; C057619:glimepiride; D000068677:Sildenafil Citrate; D065729:Cytochrome P-450 CYP2C9
keywords: Diabetic nephropathy; Glimepiride; Homology modeling; Pharmacokinetics; Schrodinger; Sildenafil citrate