Pathway Anti-diabetic Drug Nateglinide Pathway, Pharmacokinetics

Nateglinide metabolism and transport in liver cell
Anti-diabetic Drug Nateglinide Pathway, Pharmacokinetics
nateglinide nateglinide slco1b1 cyp2c9 cyp3a4 cyp2c9 cyp3a4
clickable pathway icons


Nateglinide is an anti-diabetic drug that belongs to the meglitinide category. It helps to lower blood glucose levels by blocking ATP-dependent potassium channels in pancreatic beta cells, which in turn, stimulates insulin secretion. Similar to repaglinide, nateglinide also has a rapid onset and short duration of action. It has been used alone or in combination with other medications to treat patient with type 2 diabetes.

Nateglinide is administered 0-30 minutes before meals as a meal time glucose regulator. It is rapidly absorbed from the gastrointestinal tract and undergoes extensive biotransformation in liver to at least nine metabolites. Of the 9 metabolites, the majority of them are hydroxylation products with M1 as the predominant metabolite which is monohydroxylated at the methane carbon. These major metabolites have much less anti-diabetic activity than nateglinide. The only metabolite that possesses significant pharmacological activity is the isoprene metabolite M7. However, due to low abundance of M7 (<7%), the vast majority of the pharmacological effect is attributed to the parent compounds. Nateglinide is excreted predominantly in urine as metabolites, with only 16% of the dose excreted unchanged. In vitro inhibition experiments with human hepatic microsomes and recombinant human cytochrome P450s suggest the involvement of mainly CYP2C9, and to a lesser extent CYP3A4, in nateglinide metabolism. Patients carrying the CYP2C9*3 alleles have significantly reduced clearance of nateglinide and may have increased risk for hyperglycemia. Similar to repaglinide, genetic polymorphism in hepatic-uptake transporter SLCO1B1 (OATP1B1) is another independent determinant of the pharmacokinetics of nateglinide.

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
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Therapeutic Categories:
  • Endocrine and Metabolic Disease agents

Entities in the Pathway

Genes (3)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
M1 M11 11259325
M1 M12 11259325
M2 M11 11259325
M2 M12
M3 M11 11259325
M3 M12 11259325
M7 M11
M7 M12
nateglinide M1 CYP2C9, CYP3A4 11259325, 14748619, 16372821
nateglinide M2 CYP2C9, CYP3A4 11259325
nateglinide M3 CYP2C9, CYP3A4 11259325
nateglinide M4 11259325
nateglinide M5 11259325
nateglinide M6 11259325
nateglinide M7 11259325
nateglinide nateglinide SLCO1B1 16796707, 18187595

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