Description
Glyburide (10238-21-8) is a second generation oral hypoglycemic agent. Acts via ATP-dependent K+ channel (Kir6, KATP) block.1?Inhibits Kir6 currents in the pancreas, causing an increase in intracellular Ca2+ and insulin secretion. Glyburide also inhibits recombinant CFTR Cl- channels with an IC50 of 20 μM.2?Cell permeable.
Originator
Daonil,Hoechst,Germany
Definition
ChEBI: An N-sulfonylurea that is acetohexamide in which the acetyl group is replaced by a 2-(5-chloro-2-methoxybenzamido)ethyl group.
Manufacturing Process
To a solution of 10.2 g of 4-(β-(2-ethoxy-5-chlorobenzamido)ethyl)-
benzenesulfonamide in 12.5 ml of 2 N sodium hydroxide solution and 30 ml
acetone are added dropwise, at 0-5°C, 3.3 g of cyclohexyl isocyanate. The
whole is stirred for 3 hours, diluted with water and methanol, undissolved
matter is separeted by filtration. The filtrate is acidified with dilute
hydrochloric acid. The 4-(β-(2-ethoxy-5-chlorobenzamido)ethyl)-
benzenesulfonyl)-N'-cyclohexylurea which precipitates in the form of crystals
melts after recrystallization from methanol at 168-170°C.
Brand name
Micronase (Pharmacia & Upjohn).
Therapeutic Function
Oral hypoglycemic
General Description
Glyburide (glibenclamide) is 5-chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxybenzamide; this compound can also be named asthe urea—see preceding discussion (Diabeta, Glynase,generic). Some tablet formulations contain micronized drug(formerly Micronase, now only generic). Combinations areavailable with metformin in the United States (Glucovance,generic; tablets, mg glipizide/mg metformin as hydrochloride:1.25/250, 2.5/500, 5/500).
General Description
Similar to glipizide, glyburide, 1-[[p-[2-(5-chloro-o-anisamido)ethyl]-phenyl]sulfonyl]-3-cyclohexylurea(DiaBeta, Micronase, Glynase), is a second-generationoral hypoglycemic agent. The drug has a half-life eliminationof 10 hours, but its hypoglycemic effect remains for upto 24 hours.
Biological Activity
ATP-dependent K + channel (K ATP ) and CFTR Cl - channel blocker. Inhibits K ATP currents in the pancreas, causing an increase in intracellular Ca 2+ and insulin secretion. Inhibits recombinant CFTR Cl- channels with an IC 50 of 20 μ M.
Biochem/physiol Actions
Selectively blocks ATP-sensitive K+ channels; high affinity binding sites found in brain, pancreatic β cells, and cardiovascular system.
Mechanism of action
This drug belongs to the second-generation sulfonylurea derivatives. Like all of the other
oral hypoglycemic drugs examined, it is a β-cell stimulant in pancreas; but on the other
hand, it increases the sensitivity to insulin, the degree to which it binds with target cells.
At the same time, it differs in that it is easier to tolerate. The hypoglycemic effect sets in at significantly lower doses than with first-generation drugs.
Clinical Use
Non-insulin dependent diabetes mellitus
Synthesis
Glyburide, 1-[4-[2-(5-chloro-2-methoxybenzamido)ethyl]-phenylsulfonyl]-3-
cyclohexylurea (26.2.11), is a second-generation drug that differs from those described above
in that it has a more complex structure in the sulfonylamide region of the molecule into which
an additional pharmacophore group is added. It is synthesized from 2-methoxy-5-chlorobenzoic
acid chloride, which is transformed into an amide 26.2.9 by reacting it with 2-phenylethylamine.
This undergoes subsequent sulfonylchlorination by chlorosulfonic acid, and then
amination by ammonia, which gives sulfonamide 26.2.10. The resulting sulfonamide is
reacted with cylclohexylisocyanate to give the desired glyburide (26.2.11).
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: effects enhanced by NSAIDs.
Antibacterials: effects enhanced by chloramphenicol,
sulphonamides, tetracyclines and trimethoprim;
effects possibly enhanced by ciprofloxacin and
norfloxacin; effect reduced by rifamycins.
Anticoagulants: effect possibly enhanced by
coumarins; also possibly changes to INR.
Antifungals: concentration increased by fluconazole
and miconazole and possibly voriconazole.
Bosentan: increased risk of hepatoxicity - avoid.
Ciclosporin: may increase ciclosporin levels.
Lipid-regulating drugs: absorption reduced by
colesevelam; concentration possibly increased by
fluvastatin; possibly additive hypoglycaemic effect
with fibrates.
Sulfinpyrazone: enhanced effect of sulphonylureas.
Metabolism
Glibenclamide is metabolised, almost completely, in the
liver, the principal metabolite being only very weakly
active.
About 50% of a dose is excreted in the urine and 50% via
the bile into the faeces.
References
1) Brogden et al. (1979), Glipizide: a review of its pharmacological properties and therapeutic use; Drugs, 18 329
2) Sheppard and Welsh (1992), Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents; J. Gen. Physiol., 100 573
