Pathway Anti-diabetic Drug Repaglinide Pathway, Pharmacokinetics

Repaglinide metabolism and transport in a liver cell.
Anti-diabetic Drug Repaglinide Pathway, Pharmacokinetics
repaglinide repaglinide m1 m2 m3 m4 m0-oh slco1b1 cyp3a4 cyp2c8 cyp3a4 cyp2c8 cyp3a4 cyp3a4 cyp2c8
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Repaglinide is an antidiabetic drug that belongs to meglitinide category. The mechanism of action of repaglinide is to lower blood glucose levels by blocking ATP-dependent potassium channels in pancreatic beta cells, which in turn, stimulates insulin secretion. Repaglinide acts in a dose-dependent manner, and is characterized by a fast onset, yet short duration of action. It has been used to treat patient with type 2 diabetes alone or in combination with metformin.

Repaglinide is orally administered and rapidly absorbed from the gastrointestinal tract. It is eliminated almost completely by hepatic metabolism through oxidative biotransformation and direct conjugation with glucoronic acid. The major metabolites of repaglinide are M1 (the aromatic amine), M2 (an oxidized dicarboxylic acid) and M4 (formed via hydroxylation on the piperidine ring). These metabolites are primarily excreted via the bile into the feces and do not contribute to the glucose lowering activity of repaglinide. The cytochrome P450 enzyme CYP3A4 and CYP2C8 are the principle catalysts for repaglinide metabolism (PMID: 12919179). CYP3A4 primarily catalyzes the formation of the M1 and M2 metabolites, whileas CYP2C8 is responsible for the formation of the M4 metabolite. Polymorphism in CYP2C8 (CYP2C8*3 allele) has been shown to be associated with reduced plasma concentration of repalinide (PMID: 14534525). Genetic polymorphism in hepatic-uptake transporter SLCO1B1 (OATP1B1) is another independent determinant of the pharmacokinetics of repaglinide. The AUC of repaglinide is markedly increased in homozygous carriers of SLCO1B1 521T>C than in subjects with reference genotype 5211TT (PMID: 15961978).

Drugs that are strong inhibitor or inducers of CYP3A4, CYP2C8 or SLCO1B1 may affect pharmacokinetics of repaglinide and lead to undesirable drug-drug interaction if co-administered. The CYP3A4 inhibitors Cyclosporine and clarithromycin can markedly increase the plasma concentration of repaglinide (PMID: 16198658, 11452245). Careful monitoring of blood glucose is recommended in repaglinide-treated patients receiving strong inhibitors of CYP3A4 due to the increased risk of hypoglycemia.

Authors: Li Gong.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Therapeutic Categories:
  • Endocrine and Metabolic Disease agents

Entities in the Pathway

Genes (3)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
repaglinide M1 CYP2C8, CYP3A4 12919179
repaglinide M2 CYP2C8, CYP3A4 12919179
repaglinide M4 CYP2C8, CYP3A4 12919179, 14534525, 16390351
repaglinide M5 CYP3A4 12919179
repaglinide M0-OH CYP2C8, CYP3A4 12919179
repaglinide repaglinide SLCO1B1 15961978

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