Repaglinide is an anti-diabetic drug used as a blocker of
the ATP-sensitive potassium channels (KATP) to promote insulin
secretion and lower blood glucose levels in patients with type 2 diabetes
mellitus (T2D). In response to elevated levels of circulating
glucose; insulin is secreted from the pancreatic beta cells. This effect is
counteracted by glucagon when the glucose levels are low - the two hormones act
to maintain glucose homeostasis. The secre
tion of insulin from the
islets of Langerhans is biphasic; the first and better understood phase is
completely lost in diabetic patients while the second is severely impaired. The
first phase is largely dependent on the KATP channels. In normal
individuals, glucose is rapidly taken up by the beta cells and metabolized. The
resulting increase in ATP concentration triggers closure of KATP
channels leading to membrane depolarization and opening of voltage-gated
calcium channels. The increase in calcium concentration induces fusion of the
insulin-granules with the plasma membrane and SNARE-mediated insulin
exocytosis. Insulin binding to its receptor sets in motion the insulin pathway
which in turn activates downstream signaling pathways to regulate glucose
transport, insulin expression and a range of other gene expression and cellular
events. Repaglinide is a benzoic acid derivative of meglitinide. Meglitinide is
the non-sulfonylurea portion of glibenclamide molecule - the regulatory
subunits of KATP channel are receptors for sulfonylureas.
Repaglinide is primarily metabolized by the liver. The uptake of the drug in
the liver appears to be mediated by SLC1B1 in humans. Its processing by the
phase I biotransformation enzymes of the cytochrome P450 superfamily appears to
be carried out by distinct enzymes. There are 51 families of the cytochrome
P450 superfamily. Families 1 to 3, responsible for the metabolism of most drugs
and many xenobiotics, have low substrate specificity and have not been well
preserved during evolution. The drug appears to be metabolized in a
species-specific manner. In humans, repaglinide is metabolized by CYP2C8 and by
CYP3A4 (human genes are shown). Phase I biotransformation involves oxidation of the endogenous,
xenobiotic or drug substrate which then can be conjugated by the phase II
biotransformation (conjugation) enzymes and rendered suitable for excretion.
Transport - influx or efflux of the drug - is carried out by several carrier
and transporter families. The drug, mostly in the form of metabolites, is
excreted via bile. To see the ontology
report for annotations, GViewer and download click here [To access the PharmGKB diagram page click here]...(less)