Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor

The Journal of Pharmacology and Experimental Therapeutics
Jasminder SahiEdward L Lecluyse

Abstract

In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC50 of 200-400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 microM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 microM rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at vari...Continue Reading

References

Jan 1, 1991·Methods in Enzymology·A Parkinson, B Gemzik
Jan 1, 1996·Clinical Pharmacology and Therapeutics·J T BackmanP J Neuvonen
Jan 1, 1997·Journal of the Neurological Sciences·T KishiK Ueda
Oct 24, 1998·Genes & Development·B BlumbergR M Evans
Jul 20, 1999·The Journal of Clinical Investigation·B GreinerH K Kroemer
Apr 7, 2000·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·J SahiE L LeCluyse
Oct 24, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·D A Smith
Nov 10, 2000·International Journal of Clinical Pharmacology and Therapeutics·I MaiI Roots
Nov 25, 2000·Toxicology·J T Moore, S A Kliewer
Feb 7, 2001·Toxicological Sciences : an Official Journal of the Society of Toxicology·D G RobertsonM A Milad
Apr 12, 2001·The Journal of Biological Chemistry·A GeickO Burk
Dec 12, 2001·British Journal of Pharmacology·M D PerloffD J Greenblatt
Aug 9, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuan Hua WenVsevolod E Kostrubsky

❮ Previous
Next ❯

Citations

Jul 12, 2008·Archives of Toxicology·Olavi PelkonenHannu Raunio
Mar 18, 2005·Pharmaceutical Research·Thomayant PrueksaritanontEdward J Carlini
Aug 28, 2012·Pharmaceutical Research·Stephen D LeeKishor M Wasan
Mar 24, 2006·The New England Journal of Medicine·Steven E NissenUNKNOWN ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators
Jul 13, 2006·Current Opinion in Lipidology·Marijn C MeuweseJohn J P Kastelein
Sep 5, 2008·Molecular Pharmacology·Denise G TeoticoMatthew R Redinbo
Jan 15, 2009·American Journal of Physiology. Endocrinology and Metabolism·Ta-Yuan ChangYasuomi Urano
Mar 12, 2008·Pathophysiology of Haemostasis and Thrombosis·Stephen G WorthleyJuan J Badimon
Aug 16, 2014·European Journal of Medicinal Chemistry·Nikhilesh AryaKishor S Jain
Aug 24, 2012·Expert Opinion on Therapeutic Targets·Tao LiRonald M Evans
Mar 5, 2013·Expert Opinion on Drug Metabolism & Toxicology·Tom De BruynPieter Annaert
Oct 27, 2004·Expert Opinion on Investigational Drugs·Anthony S Wierzbicki
Aug 1, 2006·Drug Metabolism Reviews·Lesley A StanleyC Roland Wolf
Jul 26, 2006·Expert Opinion on Drug Metabolism & Toxicology·Jasminder Sahi
Apr 29, 2005·Journal of Pharmaceutical Sciences·Rommel G Tirona, Richard B Kim
Jan 3, 2009·Toxicology and Applied Pharmacology·L RichertS O Mueller
Feb 10, 2009·Journal of Biochemical and Molecular Toxicology·Jasminder SahiEdward L LeCluyse
Dec 17, 2005·Chemico-biological Interactions·Jasminder SahiLaurence H Keller
Apr 9, 2013·Journal of the American College of Cardiology·Jeffrey D WesslerRobert P Giugliano
May 22, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mika NagaiKouichi Yoshinari
Jun 18, 2011·Journal of Clinical Pharmacology·Kai-Ming DuanLi-Jun Yang
Oct 24, 2017·Biopharmaceutics & Drug Disposition·Shotaro UeharaHiroshi Yamazaki
Nov 10, 2004·Circulation·Jean-Claude TardifUNKNOWN Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators
Sep 18, 2007·Arteriosclerosis, Thrombosis, and Vascular Biology·Yukio FujiwaraRyoji Nagai
Mar 2, 2006·Biological & Pharmaceutical Bulletin·Tamihide MatsunagaShigeru Ohmori
Jan 15, 2004·The Journal of Pharmacology and Experimental Therapeutics·Jessica B MillsSonia M F de Morais
Dec 11, 2019·European Journal of Drug Metabolism and Pharmacokinetics·Yinuer HaPingping Gan
Nov 6, 2012·Expert Review of Clinical Pharmacology·Janne Hukkanen
Mar 7, 2007·Expert Review of Cardiovascular Therapy·Stephen J NichollsKeon-Woong Moon
Jul 14, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sharon L RippSonia M de Morais
Aug 31, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jasminder SahiEdward L LeCluyse

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Jasminder SahiEdward L Lecluyse
Drug Metabolism and Disposition : the Biological Fate of Chemicals
Stephanie R FaucetteEdward L Lecluyse
The New England Journal of Medicine
Lawrence L Rudel, Robert V Farese
Drug Metabolism and Disposition : the Biological Fate of Chemicals
LaToya M GriffinKim L R Brouwer
© 2022 Meta ULC. All rights reserved