|AHFS/Drugs.com||Micromedex Detailed Consumer Information|
|ATC code||A10BB09 (WHO)|
|Biological half-life||10.4 hours|
|Chemical and physical data|
|Molar mass||323.412 g/mol|
|3D model (Jmol)||Interactive image|
Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a sulfonylurea. Its classification has been ambiguous, as literature uses it as both a first-generation and second-generation sulfonylurea. Gliclazide was shown to protect human pancreatic beta-cells from hyperglycemia-induced apoptosis. It was also shown to have an antiatherogenic effect (preventing accumulation of fat in arteries) in type 2 diabetes.
Gliclazide is used for control of hyperglycemia in gliclazide-responsive diabetes mellitus of stable, mild, non-ketosis prone, type 2 diabetes. It is used when diabetes cannot be controlled by proper dietary management and exercise or when insulin therapy is not appropriate. National Kidney Foundation (2012 Update) claims that Gliclazide does not require dosage uptitration even in end stage kidney disease.
- Type 1 diabetes
- Hypersensitivity to sulfonylureas
- Severe renal or hepatic failure (But relatively useful in mild renal impairment e.g. CKD stage 3)
- Pregnancy and lactation
- Hypoglycemia - while it was shown to have the same efficacy as glimepiride, one of the newer sulfonylureas, the European GUIDE study has shown that it has approximately 50% less hypoglycaemic confirmed episodes in comparison with glimepiride.
- Gastrointestinal disturbance (reported)
- Skin reactions (rare)
- Hematological disorders (rare)
- Hepatic enzyme rises (exceptional)
Hyperglycemic action may be caused by danazol, chlorpromazine, glucocorticoids, progestogens, or β-2 agonists. Its hypoglycemic action may be potentiated by phenylbutazone, alcohol, fluconazole, β-blockers, and possibly ACE inhibitors. It has been found that rifampin increases gliclazide metabolism in humans in vivo.
Gliclazide overdose may cause severe hypoglycemia, requiring urgent administration of glucose by IV and monitoring.
Mechanism of action
Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic beta-cells. It was shown to provide cardiovascular protection as it does not bind to sulfonylurea receptors (SUR-2A) in the heart. This binding effectively closes the K+ ion channels. This decreases the efflux of potassium from the cell which leads to the depolarization of the cell. This causes voltage dependent Ca++ ion channels to open increasing the Ca++ influx. The calcium can then bind to and activate calmodulin which in turn leads to exocytosis of insulin vesicles leading to insulin release. The mouse model of MODY diabetes suggested that the reduced gliclazide clearance stands behind their therapeutic success in human MODY patients, but Urbanova et al. found that human MODY patients respond differently and that there was no consistent decrease in gliclazide clearance in randomly selected HNF1A-MODY and HNF4A-MODY patients.
- Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin sensitivity.
- Glycemia-independent hemovascular effects, antioxidant effect.
- No active circulating metabolites.
Gliclazide undergoes extensive metabolism to several inactive metabolites in human beings, mainly methylhydroxygliclazide and carboxygliclazide. CYP2C9 is involved in the formation of hydroxygliclazide in human liver microsomes and in a panel of recombinant human P450s in vitro. But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.
- Ballagi-Pordány, György; Köszeghy, Anna; Koltai, Mária-Zsófia; Aranyi, Zoltán; Pogátsa, Gábor (1990). "Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds". Diabetes Research and Clinical Practice. 8 (2): 109–14. doi:10.1016/0168-8227(90)90020-T. PMID 2106423.
- Shimoyama, Tatsuhiro; Yamaguchi, Shinya; Takahashi, Kazuto; Katsuta, Hidenori; Ito, Eisuke; Seki, Hiroyuki; Ushikawa, Kenji; Katahira, Hiroshi; et al. (2006). "Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation". Metabolism. 55 (6): 722–30. doi:10.1016/j.metabol.2006.01.019. PMID 16713429.
- Del Guerra, S; Grupillo, M; Masini, M; Lupi, R; Bugliani, M; Torri, S; Boggi, U; Del Chiaro, M; et al. (2007). "Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose". Diabetes/Metabolism Research and Reviews. 23 (3): 234–8. doi:10.1002/dmrr.680. PMID 16952202.
- Katakami, N.; Yamasaki, Y.; Hayaishi-Okano, R.; Ohtoshi, K.; Kaneto, H.; Matsuhisa, M.; Kosugi, K.; Hori, M. (2004). "Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes". Diabetologia. 47 (11): 1906–13. doi:10.1007/s00125-004-1547-8. PMID 15565373.
- "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
- Schernthaner, G.; Grimaldi, A.; Di Mario, U.; Drzewoski, J.; Kempler, P.; Kvapil, M.; Novials, A.; Rottiers, R.; et al. (2004). "GUIDE study: Double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients". European Journal of Clinical Investigation. 34 (8): 535–42. doi:10.1111/j.1365-2362.2004.01381.x. PMID 15305887.
- Park, J; Kim, KA; Park, PW; Park, CW; Shin, JG (2003). "Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide". Clinical Pharmacology & Therapeutics. 74 (4): 334–40. doi:10.1016/S0009-9236(03)00221-2. PMID 14534520.
- Lawrence, C. L.; Proks, P.; Rodrigo, G. C.; Jones, P.; Hayabuchi, Y.; Standen, N. B.; Ashcroft, F. M. (2001). "Gliclazide produces high-affinity block of K ATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells". Diabetologia. 44 (8): 1019–25. doi:10.1007/s001250100595. PMID 11484080.
- Urbanova, J.; et al. (2015). "Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a-/- Model". Current Pharmaceutical Design. 21: 5736–5748. doi:10.2174/1381612821666151008124036.
- Gopal Venkatesh Shavi et al. Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques; International Journal of Drug Delivery 2 (2010) 49-57
- Rieutord, A; Stupans, I; Shenfield, GM; Gross, AS (1995). "Gliclazide hydroxylation by rat liver microsomes". Xenobiotica. 25 (12): 1345–54. doi:10.3109/00498259509061922. PMID 8719909.
- Elliot, David J.; Lewis, Benjamin C.; Gillam, Elizabeth M. J.; Birkett, Donald J.; Gross, Annette S.; Miners, John O.; Miners, JO (2007). "Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination". British Journal of Clinical Pharmacology. 64 (4): 450–7. doi:10.1111/j.1365-2125.2007.02943.x. PMC 2048545. PMID 17517049.
- Zhang, Yifan; Si, Dayong; Chen, Xiaoyan; Lin, Nan; Guo, Yingjie; Zhou, Hui; Zhong, Dafang (2007). "Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects". British Journal of Clinical Pharmacology. 64 (1): 67–74. doi:10.1111/j.1365-2125.2007.02846.x. PMC 2000619. PMID 17298483.
- Xu, H; Williams, K M; Liauw, W S; Murray, M; Day, R O; McLachlan, A J (2009). "Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide". British Journal of Pharmacology. 153 (7): 1579–86. doi:10.1038/sj.bjp.0707685. PMC 2437900. PMID 18204476.