Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats

Xenobiotica. 2004 Feb;34(2):133-50. doi: 10.1080/00498250310001630215.


1. The consequences of extended exposure to the human immunodeficiency viral protease inhibitor ritonavir (RIT) on the expression and function of CYP3A isoforms in the liver and in enteric mucosal cells, and on the expression of the efflux transport protein P-glycoprotein (P-gp) in enteric mucosa and in brain microvessel endothelial cells, were evaluated in rat. Dexamethasone (DEX), a known inducer of CYP3A and P-gp in rodents, served as a positive control. 2. Male CD-1 rats received RIT (20 mg kg(-1)), DEX (80 mg kg(-1)) or vehicle by oral/duodenal gavage once daily for 3 days. 3. Compared with vehicle control, CYP3A activity in liver microsomes (intrinsic clearance for triazolam hydroxylation in vitro) was increased by a factor of 2-4 by RIT, and by 10-14-fold by DEX. Similar increases were observed in expression of immunoactive CYP3A protein. Overall, maximum reaction velocity and immunoactive protein were highly intercorrelated (r2 = 0.89). Both RIT and DEX also increased function and expression of enteric CYP3A, although to a more modest extent (about 1.7-fold for RIT, about 3.3-fold for DEX). 4. Enteric P-gp expression was equally induced (by 2.8-fold) by both RIT and DEX. P-gp expressed in brain microvessel endothelial cells was increased by a factor of 1.3 by both compounds. 5. Thus, increased expression of CYP3A isoforms and of P-gp occurs with 3 days of exposure to RIT in rats. Qualitatively similar changes occur in human cell culture models and in clinical studies, and might contribute to drug interactions involving RIT (and other antiretroviral agents) in humans.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Algorithms
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antibodies, Blocking / pharmacology
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood-Brain Barrier / drug effects
  • Blotting, Western
  • Capillaries / drug effects
  • Capillaries / enzymology
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Dexamethasone / pharmacology*
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • GABA Modulators / metabolism
  • Gene Expression / drug effects
  • HIV Protease Inhibitors / pharmacology*
  • Intestines / drug effects
  • Intestines / enzymology
  • Liver / drug effects
  • Liver / enzymology
  • Luminescent Measurements
  • Male
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / biosynthesis*
  • Oxidoreductases, N-Demethylating / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Ritonavir / pharmacology*
  • Triazolam / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Inflammatory Agents
  • Antibodies, Blocking
  • Enzyme Inhibitors
  • GABA Modulators
  • HIV Protease Inhibitors
  • Triazolam
  • Dexamethasone
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Ritonavir