caa a22 4500 605512388 CHVBK 20210128100655.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00894-015-2823-x doi (NATIONALLICENCE)springer-10.1007/s00894-015-2823-x Does glimepiride alter the pharmacokinetics of sildenafil citrate in diabetic nephropathy animals: investigating mechanism of interaction by molecular modeling studies [Elektronische Daten] [Alok Tripathi, Ajay Timiri, Papiya Mazumder, Anil Chandewar] 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 (60mgkg−1, i.p.) and was confirmed by assessing blood and urine biochemical parameters 28days after induction. Selected DN animals were used to explore the drug interaction between GLIM (0.5mgkg−1, p.o.) and SIL (2.5mgkg−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. Springer-Verlag Berlin Heidelberg, 2015 Diabetic nephropathy nationallicence Glimepiride nationallicence Sildenafil citrate nationallicence Pharmacokinetics nationallicence Homology modeling nationallicence Schrodinger nationallicence Asn : Asparagine nationallicence Arg : Arginine nationallicence BLAST : Basic local alignment search tool nationallicence cGMP : Cyclic guanosine mono phosphate nationallicence CYP2C9 : Cytochrome P 450 2C9 nationallicence CYP3b4 : Cytochrome P 450 3b4 nationallicence Cys : Cysteine nationallicence DN : Diabetic nephropathic nationallicence HPLC : High pressure liquid chromatography nationallicence GFR : Glomerular filtration rate nationallicence GLIM : Glimepiride nationallicence Gly : Glycine nationallicence Leu : Leucine nationallicence Lys : Lysine nationallicence NO : Nitric oxide nationallicence OPLS : Optimized potentials for liquid simulations nationallicence Phe : Phenylalanine nationallicence SIL : Sildenafil citrate nationallicence STZ : Streptozotocin nationallicence Tyr : Tyrosine nationallicence Val : Valine nationallicence Tripathi Alok Department of Pharmacology, P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija Nagar, 445001, Yavatmal, MS, India aut Timiri Ajay Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, 835215, Ranchi, Jharkhand, India aut Mazumder Papiya Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, 835215, Ranchi, Jharkhand, India aut Chandewar Anil Department of Pharmaceutical Chemistry, P. Wadhwani College of Pharmacy, 445001, Yavatmal, Maharashtra, India aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-10 1610-2940 21:10<1 2015 21 894 https://doi.org/10.1007/s00894-015-2823-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2823-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tripathi Alok Department of Pharmacology, P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija Nagar, 445001, Yavatmal, MS, India aut NATIONALLICENCE 700 1- Timiri Ajay Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, 835215, Ranchi, Jharkhand, India aut NATIONALLICENCE 700 1- Mazumder Papiya Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, 835215, Ranchi, Jharkhand, India aut NATIONALLICENCE 700 1- Chandewar Anil Department of Pharmaceutical Chemistry, P. Wadhwani College of Pharmacy, 445001, Yavatmal, Maharashtra, India aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/10(2015-10-01), 1-10 1610-2940 21:10<1 2015 21 894