Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers

J Clin Pharmacol. 1999 Jan;39(1):91-6. doi: 10.1177/00912709922007499.

Abstract

Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Biological Availability
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Injections, Intravenous
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Metabolic Clearance Rate / drug effects
  • Rifampin / pharmacology*
  • Tacrolimus / blood
  • Tacrolimus / pharmacokinetics*

Substances

  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Rifampin
  • Tacrolimus