Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants

Clin Pharmacol Ther. 2011 Mar;89(3):416-21. doi: 10.1038/clpt.2010.266. Epub 2011 Jan 26.

Abstract

We evaluated the effect of the pregnane X receptor (PXR) agonist rifampin on metformin pharmacokinetics, organic cation transporter 1 (OCT1) and OCT2 mRNA levels, and glucose levels, using the oral glucose tolerance test (OGTT) in 16 healthy subjects. The glucose-lowering effects of metformin were evaluated by OGTT before and after metformin treatment on days 1 and 2 and again on days 13 and 14 after a 10-day course of rifampin. Rifampin increased the difference in maximum glucose levels (ΔG(max)) by 41.9% (P = 0.024) and the area under the concentration-time curve (AUC) during the first 60 min after glucose ingestion (ΔAUC(gluc60)) by 54.5% (P = 0.020). Renal clearance (CL(R)) of metformin was increased by 16% (P = 0.008), but the systemic exposure was only slightly increased (13%, P = 0.049), possibly because of increased absorption. Rifampin increased OCT1 mRNA levels 4.1-fold in peripheral blood cells (P = 0.001); however, OCT2 mRNA was not detected. Our results suggest that rifampin increases OCT1 expression and hepatic uptake of metformin, leading to enhanced glucose-lowering action.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibiotics, Antitubercular / pharmacology
  • Area Under Curve
  • Blood Glucose / drug effects
  • Drug Interactions
  • Female
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Liver / metabolism
  • Male
  • Metformin / pharmacokinetics*
  • Metformin / pharmacology
  • Octamer Transcription Factor-1 / drug effects
  • Octamer Transcription Factor-1 / genetics*
  • Organic Cation Transport Proteins / drug effects
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transporter 2
  • Pregnane X Receptor
  • Prospective Studies
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Steroid / agonists
  • Rifampin / pharmacology*
  • Time Factors
  • Young Adult

Substances

  • Antibiotics, Antitubercular
  • Blood Glucose
  • Hypoglycemic Agents
  • Octamer Transcription Factor-1
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Steroid
  • SLC22A2 protein, human
  • Metformin
  • Rifampin