INFLUENCE OF NEVIRAPINE ON THE PHARMACODYNAMICS AND PHARMACOKINETICS OF REPAGLINIDE IN RATS AND RABBITS

Sagarika Majhi; Lubhan Singh

doi:10.31069/japsr.v2i3.3

Sagarika Majhi I.T.S College of Pharmacy, Muradnagar, Ghaziabad (201206), Uttar Pradesh, India.
Lubhan Singh Associate Professor, Kharvel Subharti College of Pharmacy, Swami Vivekananda Subharti University, Meerut, Uttar Pradesh, India

DOI https://doi.org/10.31069/japsr.v2i3.3

Abstract

Introduction: Management of HIV/AIDS is gradually expanding to include the chronic and metabolic complications and the adverse effects associated with its treatments like Type II diabetes mellitus. Repaglinide is a novel oral hypoglycemic agent chemically unrelated to sulphonylureas, metformin or acarbose used for the treatment of type II diabetes. Nevirapine is widely used non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection. Objective: The objective of this study was to examine the effect of oral administration of nevirapine on blood glucose and investigate their effect on the activity of repaglinide and to evaluate the safety and effectiveness of the combination. Materials and Methods: Studies in normal, diabetic rats and normal rabbits were conducted with oral doses of repaglinide, nevirapine and their combination. All the animals were fasted for 18 h prior to experimentation; during this period the animals were fed with water ad libitum. The blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours in rats by retro orbital puncture and by marginal ear vein puncture in rabbits at different time intervals. Further, the samples were analyzed for glucose by glucose oxidase/peroxidase (GOD/POD) method. The rabbit blood samples were analyzed by HPLC for serum repaglinide concentration. The serum repaglinide levels and pharmacokinetic parameters of repaglinide were evaluated with multiple dose treatments of nevirapine in rabbits. Result and Discussion: Nevirapine alone have no significant effect on the blood glucose level in rats and rabbits. Repaglinide produced hypoglycemic and antihyperglycemic activity in normal and diabetic rats with peak activity at 2 h and hypoglycemic activity in normal rabbits at 1.5 h. In combination, nevirapine reduced the effect of repaglinide in rats and rabbits. The interaction was found to be significant at both pharmacodynamic as well as at pharmacokinetic levels. Conclusion: Thus, it can be concluded that the combination of nevirapine and repaglinide may need dose adjustment and care should be taken when the combination is prescribed for their clinical benefit in diabetic patients. However, further studies are warranted.

Keywords: Repaglinide, Nevirapine, Diabetes mellitus, Drug interaction

Downloads

Download data is not yet available.

References

1. Kuhlmann J, Muck W. Clinical-pharmacological strategies to assess drug interaction potential during drug development. Drug Safety. 2001; 24:715-725.
2. Verspohl EJ. Pharmacodynamic interactions between drugs. Medizininische Monatsschrift fur Pharmazeuten. 1980; 3:228-240.
3. Goldberg RM, Mabee J, Chan L, Wong S. Drug-drug and drug-disease interactions in the ED: analysis of a high-risk population. American Journal of Emerging Medicine. 1996; 14:447-450.
4. Kohler GI, Bode-Boger SM, Busse R, Hoopmann M, Welte T, Boger RH. Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use. International Journal of Clinical Pharmacology and Therapeutics. 2000; 38:504-513.
5. Pelkonen O. Human CYPs: in vivo and clinical aspects. Drug Metabolism Reviews. 2002; 34:37-46.
6. Kremers P. Can drug-drug interactions be predicted from in vitro studies? Scientific World Journal. 2002; 2:751-766.
7. Lin JH. Tissue distribution and pharmacodynamics: a complicated relationship. Current Drug Metabolism. 2006; 7:39-65.
8. Borda IT, Slone D, Jick H. Assessment of adverse reactions within a drug surveillance program. Jama. 1968; 205:645-647.
9. Costa AJ. Potential drug interactions in an ambulatory geriatric population. Family Practice. 1991; 8:234-236.
10. Narayan KMV, Zhang P, Kanaya AM, Williams DE, Engelgau MM, Imperatore G, Ramachandran A.“Diabetes: The Pandemic and Potential Solutions.” In Disease Control Priorities in Development Countries, 2nd ed. Jamison DT, Breman JG, Measham AG, Alleyne G, Claeson M, Evans DB, Jha P, Mills A, and Musgrove P. 591-603. New York: Oxford University Press.
11. Gromada J, Dissing S, Kofod H, Jensen JFE. Effects of the hypoglycemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat beta pancreatic cells. Diabetologia. 1995; 38:1025-1032
12. Balfour JA, Faulds D. Repaglinide. Drugs & Aging. 1998; 13: 173-180.
13. Guay DR. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy.1998; 18:1195-1204.
14. Currier JS. How to manage metabolic complications of HIV therapy: what to do while we wait for answers. AIDS Read.2000; 10:1003.
15. Moylett EH. HIV: clinical manifestations. Journal of Allergy and Clinical Immunology. 2002; 110:3–16.
16. Yanovski JA, Miller KD, Kino T, Friedman TC, Chrousos GP, Tsigos C, Falloon J. Endocrine and metabolic evaluation of human immunodeficiency virus–infected patients with evidence of protease inhibitor–associated lipodystrophy. Journal of Clinical Endocrinology and Metabolism. 1999; 84:1925–1931.
17. Perrone C, Bricaire F, Leport C, Assan D, Vilde JL, Assan R. Hypoglycemia and diabetes mellitus following parenteral pentamidine mesylate administration in AIDS patients. Diabetic Medicine.1990; 7:585–589.
18. Danoff A. Endocrinologic complications of HIV infection. Medical Clinics of North America.1996; 80:1453–1469.
19. Chen D. Lipodystrophy in human immunodeficiency virus–infected patients. Journal of Clinical Endocrinology and Metabolism. 2002; 84:4845–4856.
20. Stenzel MS, Carpenter CCJ. The management of the clinical complications of antiretroviral therapy. Infectious Disease Clinics of North America. 2000; 14: 851–878.
21. Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PWF, Agostino RBD, Grinspoon S. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clinical Infectious Diseases. 2001; 32: 130–139.
22. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS.1998; 12:F51–F58.
23. Vigouroux C, Gharakhanian S, Salhi Y, Nguyen TH, Chevenne D, Capeau J, Rozenbaum W. Diabetes, insulin resistance and dyslipidemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metabolism.1999; 25: 225–232.
24. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20636s025,20933s014lbl.pdf. Accessed on: 01/July/2019
25. Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A: Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International DiabetesFoundation and Adult Treatment Panel III criteria. Diabetes Care. 2007; 30(1):113-119.
26. Paget GE, Barnes JM: From toxicity tests. In evaluation of drug activities: pharmacometrics Volume 1. Edited by: Laurence DR, Bacharach AL. London: Academic Press; 1964:50-161.
27. Ramachandra SS, Bheemachari, Joshi VG, Kumar YA, Pandit J, Rao NV, Rambhimaiah S: Influence of Itraconazole on sulfonylureas-induced hypoglycemia in diabetic rats. Indian Journal of Pharmaceutical Sciences. 2005; 67(6): 677- 680.
28. Trinder P: Determination of glucose in blood using glucose oxidase with an alternative glucose acceptor. Annals of Clinical Biochemistry. 1969; 6: 24-27.
29. Dhanabal SP, Kokate CK, Ramanathan M, Elango K, Kumar EP, Subbaraj T, Manimaran S, Suresh B: Antihyperglycemic activity of Polygala arvensis in alloxan diabetic rats. Indian Drugs. 2004; 41(11): 690-695.
30. Vetrichelvan T, Kavimani S, Gupta JK, Lakshmi NC: Eff ect of rifampicin on Trigonella Foenum Graecum (Fenugreek) induced hypoglycemia in rats. Indian Journal of Pharmaceutical Sciences. 1998; 244-245.
31. Swami AM, Shetty SR, Kumar SMS, Rao NV: A study on drug-drug interaction of roxithromycin and anti-diabetic drugs. Indian Drugs. 2005; 42(12): 808-813.
32. Satyanarayana S, Krishnaiah YSR, Eswar KK, Elisha IR, Kiran VVSK: Influence of quinidine, selegiline and amphotericin-B on the pharmacokinetics and pharmacodynamics of tolbutamide in rabbits. Indian Drugs.1998; 35(10): 640-644.
33. Scheen AJ, Lefebvre PJ. Pathophysiology of type 2 diabetes. In: Kuhlmann J, Puls W, editors. Handbook of experimental pharmacology: oral antidiabetics. Berlin: Springer Verlag, 1995: 7-42.
34. Riska P, Lamson M, MacGregor T. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metabolism and Disposition. 1999; 27: 895-901.
35. Bidstrup TB, Bjornsdottir I, Sidelman UG. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. British Journal of Clinical Pharmacology. 2003; 56: 305-314.
36. Abu Bakar R, MohdSuhaimiAW, Ahmad I, Zabidah I, Siew HG. Method development and validation of repaglinide in human plasma by HPLC and its application in pharmacokinetic studies. Journal of Pharmaceutical and Biomedical Analysis. 2007; 43:1831-1835.