Tripathi Alok Shiomurti, Timiri Ajay Kumar, Mazumder Papiya Mitra, Chandewar Anil
Department of Pharmacology, P. Wadhwani College of Pharmacy, Dhamangaon Road, Girija Nagar, Yavatmal, MS, 445001, India.
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India, 835215.
J Mol Model. 2015 Oct;21(10):276. doi: 10.1007/s00894-015-2823-x. Epub 2015 Oct 1.
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.
本研究评估了格列美脲（GLIM）与枸橼酸西地那非（SIL）在链脲佐菌素（STZ）诱导的糖尿病肾病（DN）动物中的可能药物相互作用，并基于分子建模研究推测了相互作用的可能机制。通过单次腹腔注射STZ（60 mg kg⁻¹）诱导糖尿病肾病，并在诱导后28天通过评估血液和尿液生化参数进行确认。在实验方案的第29天和第70天，选用DN动物探索GLIM（0.5 mg kg⁻¹，口服）和SIL（2.5 mg kg⁻¹，口服）之间的药物相互作用。通过使用高效液相色谱 - 紫外法评估血浆药物浓度来评估可能的药物相互作用，并测定血液和尿液中生化参数的变化。使用薛定谔软件的Maestro模块通过分子建模研究结果推测相互作用的机制。由于STZ处理组的血液和尿液生化参数有显著改变，糖尿病肾病得到确认。在实验方案的第70天，与GLIM共同给药时，大鼠血浆中SIL的浓度显著增加（P < 0.001）。分子建模揭示了与大鼠血清白蛋白和CYP2C9的重要相互作用。与SIL相比，GLIM与大鼠血清白蛋白的结合位点残基有很强的疏水相互作用，而对于CYP2C9，GLIM与极性接触和疏水相互作用形成的氢键比SIL更强。本研究得出结论，在DN动物的管理中，SIL与GLIM长期共同给药时生物利用度增加，且分子建模研究支持该机制。
