ets 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 K_ATP channels. In normal individuals, glucose is rapidly taken up by the beta cells and metabolized. The resulting increase in ATP concentration triggers closure of K_ATP 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. Nateglinide is a D-phenylalanine derivative usually referred to as a meglitinide analog by virtue of functional rather than structural relationships. Meglitinide is the non-sulfonylurea portion of glibenclamide molecule - the regulatory subunits of K_ATP channel are receptors for sulfonylureas. Nateglinide is primarily metabolized by the liver. The uptake of the drug in the liver appears to be mediated by SLC1B1 in humans. Intestinal absorption in rat brush-border membrane and human Caco-2 cells indicate the involvement of a H⁺ dependent cotransport system. 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 drugs appear to be metabolized in a species-specific manner. In humans, nateglinide is metabolized by CYP2C9 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 primarily excreted in the urine. To see the ontology report for annotations, GViewer and download click here[To access the PharmGKB diagram page click here]...(less)