Gliclazide

Not to be confused with glipizide or glyburide.
Gliclazide
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • AU: C
ATC code A10BB09 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
Pharmacokinetic data
Biological half-life 10.4 hours
Identifiers
CAS Number 21187-98-4 YesY
PubChem (CID) 3475
DrugBank DB01120 YesY
ChemSpider 3356 YesY
UNII G4PX8C4HKV YesY
KEGG D01599 YesY
ChEBI CHEBI:31654 YesY
ChEMBL CHEMBL427216 YesY
ECHA InfoCard 100.040.221
Chemical and physical data
Formula C15H21N3O3S
Molar mass 323.412 g/mol
3D model (Jmol) Interactive image
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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 [1] and second-generation[2] sulfonylurea. Gliclazide was shown to protect human pancreatic beta-cells from hyperglycemia-induced apoptosis.[3] It was also shown to have an antiatherogenic effect (preventing accumulation of fat in arteries) in type 2 diabetes.[4]

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[5]

Medical uses

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.

Contraindications

Adverse effects

Interactions

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.[7]

Overdosage

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.[8] 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.[9]

Properties

Water Solubility = 0.027 mg/L[10]

Metabolism

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.[11][12] But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.[13][14]

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Gopal Venkatesh Shavi et al. Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques; International Journal of Drug Delivery 2 (2010) 49-57
  11. ↑ 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.
  12. ↑ 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 2048545Freely accessible. PMID 17517049.
  13. ↑ 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 2000619Freely accessible. PMID 17298483.
  14. ↑ 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 2437900Freely accessible. PMID 18204476.
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