Therapeutic Drug Monitoring, CYP2C9 Genotyping and Phenotyping in the Treatment of Diabetes with Glibenclamide Products

Rational use of glybenclamide products in the treatment of patients with type 2 diabetes remains a high-priority task. The paper offers a summary of the main groups of glibenclamide drugs and describes pharmacogenetics of glybenclamide. Glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9). Individuals with genetically determined low CYP2C9 activity are at an increased risk of hypoglycaemia. Carriers of CYP2C9*3 and CYP2C9*2 alleles tend to have higher concentrations of glybenclamide in blood and increased insulin secretion. Pharmacogenetic testing of patients and drug concentration monitoring using HPLC-MS can help reduce the risk of hypoglycemia during glibenclamide treatment. Based on literature review the authors selected the method characterised by a simple sample preparation procedure, short analysis time, and a wide analytical range for the substances being determined. This method can be useful both for bioequivalence studies and evaluation of glibenclamide products interchangeability. Glibenclamide pharmacokinetics is characterised by high interindividual variability. This may lead to both an increased risk of hypoglycemia and drug inefficacy, therefore, when prescribing glibenclamide, a physician should carefully control the efficacy and safety of drug therapy.

1. Dedov II, Shestakova MV, Mayorov AYu, eds. Standards of specialized diabetes care. 9th ed. Moscow; 2019 (In Russ.) https://doi.org/10.14341/DM221S1

2. Zoppi M, Braunschweig S, Kuenzi UP, Maibach R, Hoigne R. Incidence of lethal adverse drug reactions in the comprehensive hospital drug monitoring, a 20-year survey, 1974-1993, based on the data of Berne/St. Gallen. Eur J Clin Pharmacol. 2000;56(5):427-30. https://doi.org/10.1007/s002280000158

3. Sartor G, Melander A, Schersten B, Wahlin-Boll E. Serum gli-benclamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide. Diabetologia. 1980;18(1):17-22. https://doi.org/10.1007/bf01228296

4. Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, et al. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther. 2002;71(4):286-96. https://doi.org/10.1067/mcp.2002.122476

5. Surendiran A, Pradhan SC, Agrawal A, Subrahmanyam DK, Rajan S, Anichavezhi D, et al. Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients. Eur J Clin Pharmacol. 2011;67(8);797-801. https://doi.org/10.1007/s00228-011-1013-8

6. Hartmann B, Czock D, Keller F. Drug therapy in patients with chronic renal failure. Dtsch Arztebl Int. 2010;107(37):647-55. https://doi.org/10.3238/arztebl.2010.0647

7. Sanchez-Nava LA, Bautista-Sanchez U, Robles-Piedras AL. Pharmaceutical equivalence and similarity studies of glibenclamide tablets. GSC Biological and Pharmaceutical Sciences. 2019;07(01):096-101. https://doi.org/10.30574/gscbps.2019.7.1.0053

8. Shokhin IE, Ramenskaya GV, Vasilenko GF, Malashenko EA. Biopharmaceutical properties and comparative dissolution kinetics of glibenclamide generics. Voprosy biologicheskoy, meditsinskoy i farmatsevticheskoy khimii = Problems of Biological, Medical and Pharmaceutical Chemistry. 2009;(6):36-8 (In Russ.)

9. Reikhart DV. Investigation of the bioequivalence of drugs in Russia. Farmatsiya = Pharmacy. 2010;(3):5-8 (In Russ.)

10. Rydberg T, Jonsson A, Melander A. Comparison of the kinetics of glyburide and its active metabolites in humans. J Clin Pharm Ther. 1995;20(5):283-95. https://doi.org/10.1111/j.1365-2710.1995.tb00664.x

11. Gravel S, Chiasson JL, Turgeon J, Grangeon A, Michaud V. Modulation of CYP450 activities in patients with type 2 diabetes. Clin Pharmacol Ther. 2019;106(6):1280-9. https://doi.org/10.1002/cpt.1496

12. Yasar U, Forslund-Bergengren C, Tybring G, Dorado P, Llerena A, Sjoqvist F, et al. Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther. 2002;71(1):89-98. https://doi.org/10.1067/mcp.2002.121216

13. Dorado P, Machi'n E, de Andres F, Naranjo ME, Penas-Lledo EM, Llerena A. Development of a HPLC method for the determination of losartan urinary metabolic ratio to be used for the determination of CYP2C9 hydroxylation phenotypes. Drug Metabol Drug Interact. 2012;27(4):217-33. https://doi.org/10.1515/dmdi-2012-0018

14. Tanaka S, Uchida S, Inui N, Takeuchi K, Watanabe H, Namiki N. Simultaneous LC-MS/MS analysis of the plasma concentrations of a cocktail of 5 cytochrome P450 substrate drugs and their metabolites. Biol Pharm Bull. 2014;37(1):18-25. https://doi.org/10.1248/bpb.b13-00401

15. Susanto F, Reinauer H. Glibenclamide in serum: comparison of high-performance liquid chromatography using fluorescence detector and liquid chromatography/mass spectrometry with atmospheric-pressure chemical-ionization (APCI LC/MS). Anal Bioanal Chem. 1996;356(5):352-7. https://doi.org/10.1007/s0021663560352

16. Niopas I, Daftsios AC. A validated high-performance liquid chromatographic method for the determination of gliben-clamide in human plasma and its application to pharmacokinetic studies. J Pharm Biomed Anal. 2002;28(3-4):653-7. https://doi.org/10.1016/s0731-7085(02)00013-4

17. AbuRuz S, Millership J, McElnay J. The development and validation of liquid chromatography method for the simultaneous determination of metformin and glipizide, gliclazide, glibenclamide or glim-peride in plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;817(2):277-86. https://doi.org/10.1016/j.jchromb.2004.12.018

18. Venkatesh P, Harisudhan T, Choudhury H, Mullangi R, Srinivas NR. Simultaneous estimation of six anti-diabetic drugs — glibenclamide, gliclazide, glipizide, pioglitazone, repaglinide and rosiglitazone: development of a novel HPLC method for use in the analysis of pharmaceutical formulations and its application to human plasma assay. Biomed Chromatogr. 2006;20(10):1043-8. https://doi.org/10.1002/bmc.635

19. Gedeon C, Kapur B, Aleksa K, Koren G. A simple and rapid HPLC method for the detection of glyburide in plasma original research communication (analytical). Clin Biochem. 2008;41(3):167—73. https://doi.org/10.10167j.dinbiochem.2007.07.025

20. Hess C, Musshoff F, Madea B. Simultaneous identification and validated quantification of 11 oral hypoglycaemic drugs in plasma by electrospray ionisation liquid chromatography-mass spectrometry. Anal Bioanal Chem. 2011;400(1):33-41. https://doi.org/10.1007/s00216-011-4698-8

21. Lakshmi KS, Rajesh T. Separation and quantification of eight antidiabetic drugs on a high-performance liquid chromatography: its application to human plasma assay. ISRN Pharm. 2011;2011:521353. https://dx.doi.org/10.5402%2F2011%2F521353

22. Binz TM, Villani N, Neels H, Schneider S. Rapid extraction, identification and quantification of oral hypoglycaemic drugs in serum and hair using LC-MS/MS. Forensic Sci Int. 2012;223(1-3):1 19-24. https://doi.org/10.1016/j.forsciint.2012.08.014

23. Zhang X, Wang X, Vernikovskaya DI, Fokina VM, Nanovskaya TN, Hankins GD, et al. Quantitative determination of metformin, glyburide and its metabolites in plasma and urine of pregnant patients by LC-MS/MS. Biomed Chromatogr. 2015;29(4):560-9. https://doi.org/10.1002/bmc.3314