Impact of efavirenz on intestinal metabolism and transport: insights from an interaction study with ezetimibe in healthy volunteers

Clin Pharmacol Ther. 2012 Mar;91(3):506-13. doi: 10.1038/clpt.2011.255. Epub 2012 Feb 1.

Abstract

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adult
  • Alkynes
  • Animals
  • Anticholesteremic Agents / pharmacokinetics*
  • Anticholesteremic Agents / pharmacology
  • Azetidines / pharmacokinetics*
  • Azetidines / pharmacology
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / pharmacology*
  • Biological Transport / drug effects
  • Cell Line
  • Cell Line, Transformed
  • Cyclopropanes
  • Cytochrome P-450 CYP3A / metabolism
  • Dogs
  • Drug Interactions
  • Ezetimibe
  • Gene Expression / drug effects
  • Glucuronosyltransferase / antagonists & inhibitors
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • HEK293 Cells
  • HIV Infections / drug therapy
  • Humans
  • Hypercholesterolemia / drug therapy
  • Intestinal Absorption / drug effects
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects*
  • Liver / drug effects
  • Liver / metabolism
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism
  • RNA, Messenger / genetics
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkynes
  • Anticholesteremic Agents
  • Azetidines
  • Benzoxazines
  • Cyclopropanes
  • Liver-Specific Organic Anion Transporter 1
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • RNA, Messenger
  • SLCO1B1 protein, human
  • multidrug resistance-associated protein 2
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Ezetimibe
  • efavirenz