Comparison of pharmacokinetic parameters of ranolazine between diabetic and non-diabetic rats

Document Type : Original Article


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

5 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

6 Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

7 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

8 Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Diabetes mellitus (DM) affects the pharmacokinetics of drugs. Ranolazine is an antianginal drug that is prescribed in DM patients with angina. We decided to evaluate the effect of DM on the pharmacokinetics of ranolazine and its major metabolite CVT-2738 in rats.
Materials and Methods: Male rats were divided into two groups: DM (induced by 55 mg/kg Streptozotocin (STZ)) and non-DM. All animals were treated with 80 mg/kg of ranolazine for 7 continuous days. The blood samples were collected immediately at 0 (prior to dosing), 1, 2, 3, 4, 8, and 12 hr after administration of the 7th dose of ranolazine. Serum ranolazine and CVT-2738 concentrations were determined using the high-performance liquid chromatography (HPLC) method. Pharmacokinetic parameters were calculated using a non-compartmental model and compared between the two groups.
Results: The peak serum concentration (Cmax) and area under the curve (AUC) of ranolazine significantly decreased in DM compared with non-DM rats. DM rats showed significantly higher volumes of distribution (Vd) and clearance (CL) of ranolazine than non-DM rats. DM did not affect Ke, Tmax, and T1/2 of ranolazine. The concentration of metabolite was lower than the HPLC limit of detection (LOD).
Conclusion: It was found that streptozotocin-induced DM increased Vd and CL of ranolazine, thereby decreasing the AUC of the drug. Therefore, dosage adjustment may be necessary for DM patients, which requires further clinical studies.


1. Mashayekhi-Sardoo H, Mohammadpour AH, Nomani H, Sahebkar A. The effect of diabetes mellitus on pharmacokinetics, pharmacodynamics and adverse drug reactions of anticancer drugs. J Cell Physiol 2019; 234:19339-19351.
2. Vahabzadeh M, Mohammadpour A-H. Effect of diabetes mellitus on the metabolism of drugs and toxins. J Clin Toxicol 2015; 5:2161-0495.1000233.
3. Mashayekhi-Sardoo H, Atkin SL, Montecucco F, Sahebkar A. Potential alteration of statin-related pharmacological features in diabetes mellitus. biomed res. Int 2021; 2021:6698743.
4. Hasler WL, Coleski R, Chey WD, Koch KL, McCallum RW, Wo JM, et al. Differences in intragastric pH in diabetic vs. idiopathic gastroparesis: relation to degree of gastric retention. Am J Physiol Gastrointest Liver Physiol 2008; 294:G1384-1391.
5. Dostalek M, Akhlaghi F, Puzanovova M. Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs. Clin. Pharmacokinet 2012; 51:481-499.
6. Hussain S. Effect of acarbose on the bioavailability and pharmacokinetics of metronidazole in healthy and diabetic subjects. Br J Pharm Res 2012; 2:41-49.
7. Perea-Jacobo R, Muñiz-Salazar R, Laniado-Laborin R, Cabello-Pasini A, Zenteno-Cuevas R, Ochoa-Terán A. Rifampin pharmacokinetics in tuberculosis-diabetes mellitus patients: a pilot study from Baja California, Mexico. Int J Tuberc Lung Dis 2019; 23:1012-1016.
8. Mohd Sazlly Lim S, Sinnollareddy M, Sime FB. Challenges in Antifungal Therapy in Diabetes Mellitus. J Clin Med 2020; 1-9. Dostalek M, Court MH, Yan B, Akhlaghi F. Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus. Br. J. Pharmacol 2011; 163:937-947.
10. Cheguri S, Ajmera R, Ciddi V. Pharmacokinetic and pharmacodynamic interaction of quercetin and saxagliptin in normal and diabetic rats. Pharmacologia 2017; 8:90-94.
11. Caudle AS, Kim HJ, Tepper JE, O’Neil BH, Lange LA, Goldberg RM, et al. Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer. Ann Surg Oncol 2008; 15:1931-1936.
12. Nash DT, Nash SD. Ranolazine for chronic stable angina. The Lancet 2008; 372:1335-1341.
13. Zhao L, Li H, Jiang Y, Piao R, Li P, Gu J. Determination of ranolazine in human plasma by liquid chromatographic-tandem mass spectrometric assay. J Chromatogr Sci 2008; 46:697-700.
14. Acting Nitrates L. Abbreviated New Drug Evaluation: Ranolazine month/year of review: August 2012 End date of literature search: May 2012 Generic Name: Ranolazine Brand Name (Manufacturer): Ranexa®(CV Therapeutics).  2012.
15. Abdallah H, Jerling M. Effect of hepatic impairment on the multiple-dose pharmacokinetics of ranolazine sustained-release tablets. J Clin Pharmacol 2005; 45:802-809.
16. Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet 2006; 45:469-491.
17. Dobesh PP, Trujillo TC. Ranolazine: a new option in the management of chronic stable angina. Pharmacotherapy 2007; 27:1659-1676.
18. Babu PR, Babu KN, Peter PL, Rajesh K, Babu PJ. Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models. Drug Dev Ind Pharm 2013; 39:873-879.
19. Seedevi P, Ramu Ganesan A, Moovendhan M, Mohan K, Sivasankar P, Loganathan S, et al. Anti-diabetic activity of crude polysaccharide and rhamnose-enriched polysaccharide from G. lithophila on streptozotocin (STZ)-induced in Wistar rats. Sci Rep 2020; 10:1-12.
20. King AJF. The use of animal models in diabetes research. Br J Pharmacol 2012; 166:877-894.
21. Guideline IHT. Validation of analytical procedures: text and methodology. Q2 (R1) 2005; 1:1-13.
22. Kurmi M, Kumar S, Singh B, Singh S. Implementation of design of experiments for optimization of forced degradation conditions and development of a stability-indicating method for furosemide. J Pharm Biomed 2014; 96:135-143.
23. Taleuzzaman M. Limit of blank (LOB), limit of detection (LOD), and limit of quantification (LOQ). Organic & Medicinal Chemistry International Journal, Juniper Publishers Inc., 7: 127-131.
24. Chen L, Chen J, Lu M, Stämpfli A. Simultaneous determination of elbasvir and grazoprevir in fixed-dose combination and mass spectral characterization of each degradation product by UHPLC-ESI-QTOF-MS/MS. J. Pharm. Biomed 2020; 178:112964.
25. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 2010; 99:306-314.
26. Ahmed T. Pharmacokinetics of Drugs Following IV Bolus, IV Infusion, and Oral Administration. 2015. p. 53-89.
27. Nguyen E, Coleman CI, Kohn CG, Weeda ER. Ranolazine in patients with type 2 diabetes and chronic angina: A cost-effectiveness analysis and assessment of health-related quality-of-life. Int J Cardiol 2018; 273:34-38.
28. Yao H, Gu J, Shan Y, Wang Y, Chen X, Sun D, et al. Type 2 diabetes mellitus decreases systemic exposure of clopidogrel active metabolite through upregulation of P-glycoprotein in rats. Biochem Pharmacol 2020; 180:114142.
29. Alfarisi O, Mave V, Gaikwad S, Sahasrabudhe T, Ramachandran G, Kumar H, et al. Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment. Antimicrob Agents Chemother 2018; 62: e01383-18.
30. Adithan C, Srinivas B, Indhiresan J, Shashindran CH, Bapna JS, Thakur LC, et al. Influence of type I and type II diabetes mellitus on phenytoin steady-state levels. Int J Clin Pharmacol Ther Toxicol 1991; 29:310-313.
31. Wang Z, Gao Z, Wang A, Jia L, Zhang X, Fang M, et al. Comparative oral and intravenous pharmacokinetics of phlorizin in rats having type 2 diabetes and in normal rats based on phase II metabolism. Food Funct 2019; 10:1582-1594.
32. Mashayekhi-Sardoo H, Mohammadpour AH, Mehri S, Kamali H, Sahebkar A, Imenshahidi M. Diabetes mellitus aggravates ranolazine-induced ECG changes in rats. J Interv Card Electrophysiol 2021; 63: 379-388.
33. Tran M, Elbarbry F. Influence of diabetes mellitus on pharmacokinetics of drugs. MOJ Bioequiv Availab 2016; 2:00016.
34. Lee JH, Yang SH, Oh JM, Lee MG. Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: Comparison with those in patients with type I diabetes mellitus. J Pharm Pharmacol 2010; 62:1-23.
35. Fediuk DJ, Zhou S, Dawra VK, Sahasrabudhe V, Sweeney K. Population pharmacokinetic model for ertugliflozin in healthy subjects and patients with type 2 diabetes mellitus. Clin Pharmacol Drug Dev 2020; 10: 696–706.
36.Lee DY, Lee MG, Shin HS, Lee I. Changes in omeprazole pharmacokinetics in rats with diabetes induced by alloxan or streptozotocin: faster clearance of omeprazole due to induction of hepatic CYP1A2 and 3A1. J Pharm Pharm Sci 2007; 10:420-433.
37. Adithan C, Danda D, Swaminathan RP, Indhiresan J, Shashindran CH, Bapna JS, et al. Effect of diabetes mellitus on salivary paracetamol elimination. Clin Exp Pharmacol Physiol 1988; 15:465-471.
38. Adithan C, Danda D, Shashindran CH, Bapna JS, Swaminathan RP, Chandrasekar S. Differential effect of type I and type II diabetes mellitus on antipyrine elimination. Methods Find Exp Clin Pharmacol 1989; 11:755-758.
39. Kiriyama A, Kimura S, Banba C, Yamakawa M, Yajima R, Honbo A, et al. Pharmacokinetic-pharmacodynamic analyses of anti-diabetes, glimepiride: comparison of the streptozotocin-induced diabetic, GK, and Wistar rats. J Drug Metab Toxicol 2017; 8: 1-6.
40. Gour A, Dogra A, Sharma S, Wazir P, Nandi U. Effect of disease state on the pharmacokinetics of bedaquiline in renal-impaired and diabetic rats. ACS Omega 2021; 6: 6934-6941.
41. Robert G. Smith DPM M, RPh, CPed. Understanding How Diabetes Affects Patient Response To Medications. Podiatry Today 2012; 25:14-20.
42. Abdelsayed M, Ruprai M, Ruben PC. The efficacy of ranolazine on E1784K is altered by temperature and calcium. Sci Rep 2018; 8:1-20.
43. Meeme A, Kasozi H. Effect of glycaemic control on glomerular filtration rate in diabetes mellitus patients. Afr Health Sci 2009; 9 Suppl 1:S23-26.
44. Chiou WL. A new simple approach to study the effect of changes in urine flow and/or urine pH on renal clearance and its applications. Int J Clin Pharmacol Ther Toxicol 1986; 24:519-527.
45. Ryan JP, Irwin JA. Practical studies on urine demonstrating principles of clinical and veterinary significance. Biochem Mol Biol Educ 2002; 30:98-100.
46. Gwak EH, Yoo HY, Kim SH. Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats. Biomol Ther (Seoul) 2020; 28:361-369.
47. Wang Z, Hall SD, Maya JF, Li L, Asghar A, Gorski JC. Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans. Br J Clin Pharmacol 2003; 55:77-85.
48. Kim YC, Lee JH, Kim SH, Lee MG. Effect of CYP3A1(23) induction on clarithromycin pharmacokinetics in rats with diabetes mellitus. Antimicrob Agents Chemother 2005; 49:2528-2532.
49. Lee U, Lee I, Lee BK, Kang HE. Faster non-renal clearance of metoprolol in streptozotocin-induced diabetes mellitus rats. Eur J Pharm Sci 2013; 50:447-453.
50. Lee JH, Lee A, Oh JH, Lee YJ. Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin-induced diabetic rats. Biopharm Drug Dispos 2012; 33:474-486.