Unexpected effect of rifampin on the pharmacokinetics of linezolid: in silico and in vitro approaches to explain its mechanism

J Clin Pharmacol. 2011 Feb;51(2):229-36. doi: 10.1177/0091270010366445. Epub 2010 Apr 6.


The effect of rifampin on the steady-state pharmacokinetics of linezolid was evaluated in an open-label, multiple-dose, crossover study in 16 healthy subjects. When coadministered with rifampin, area under the plasma concentration-time curve over the dosing interval and maximum concentration values for linezolid were reduced approximately 32% and 21%, respectively. Time to maximum concentration and apparent volume of distribution were generally similar between treatments. The mean half-life and apparent oral clearance were decreased for the combination treatment compared with linezolid alone. In vitro and in silico approaches were used to evaluate this interaction. In human hepatocytes, the metabolism of linezolid was increased by 1.3- to 1.6-fold when the cells were pretreated with rifampin, compared with a 19- to 40-fold increase in testosterone metabolism, a positive control for cytochrome P4503A activity. This increase in linezolid and testosterone metabolism was partially inhibited (~50%) by ketoconazole. Modeling of these data using Simcyp suggested that rifampin inducible drug metabolizing enzymes, such as cytochrome P4503A, have a very minor contribution to linezolid clearance, which increases when rifampin is coadministered. The clinical significance of the decreased linezolid levels is unclear. Linezolid and rifampin administered alone or in combination was generally safe and well tolerated.

Publication types

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

MeSH terms

  • Acetamides / adverse effects
  • Acetamides / pharmacokinetics*
  • Adult
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / pharmacokinetics*
  • Antibiotics, Antitubercular / adverse effects
  • Antibiotics, Antitubercular / pharmacology*
  • Area Under Curve
  • Cells, Cultured
  • Computer Simulation
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / drug effects
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions
  • Enzyme Induction / drug effects
  • Half-Life
  • Hepatocytes / metabolism
  • Humans
  • Ketoconazole / pharmacology
  • Linezolid
  • Male
  • Oxazolidinones / adverse effects
  • Oxazolidinones / pharmacokinetics*
  • Rifampin / adverse effects
  • Rifampin / pharmacology*
  • Testosterone / metabolism
  • Tissue Distribution
  • Young Adult


  • Acetamides
  • Anti-Infective Agents
  • Antibiotics, Antitubercular
  • Oxazolidinones
  • Testosterone
  • Cytochrome P-450 CYP3A
  • Linezolid
  • Ketoconazole
  • Rifampin