Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
J-E ParkJ-G Shin

Abstract

Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that is mainly metabolized by cytochrome P450 (CYP) 3A4. A recent study showed that the lipid-lowering effect of statins is affected by the CYP3A5 polymorphism. Therefore, it was investigated whether CYP3A5 contributes to the metabolism of atorvastatin. Two metabolites of atorvastatin, para- and ortho-hydroxyatorvastatin, were produced by human liver microsomes and human recombinant CYP3A enzymes, and the enzyme kinetic pattern exhibited substrate inhibition. The intrinsic clearance (CL(int)) rates of para- and ortho-hydroxyatorvastatin by CYP3A4 were 2.4- and 5.0-fold of the respective CL(int) rates of CYP3A5, indicating that CYP3A4 is the major P450 isoform responsible for atorvastatin metabolism. These results suggest that atorvastatin is preferentially metabolized by CYP3A4 rather than by CYP3A5, and thus the genetic CYP3A5 polymorphism might not be an important factor in the inter-individual variation of atorvastatin disposition and pharmacodynamics in human.

References

Jan 10, 1996·JAMA : the Journal of the American Medical Association·R G Bakker-ArkemaD M Black
Aug 8, 1998·Clinical Pharmacology and Therapeutics·T KantolaP J Neuvonen
Jun 18, 2002·Molecular Pharmacology·Yvonne S LinKenneth E Thummel
Apr 11, 2003·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Robert L LinsNorbert H Lameire
Dec 3, 2003·The Pharmacogenomics Journal·T FukudaJ Azuma
Jun 1, 2004·Pharmacological Reviews·E G SchuetzM S Boguski
Jul 31, 2004·Pharmacogenetics·Kari T KivistöTimo Strandberg
Sep 24, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Weili HuangKenneth E Thummel
Oct 23, 2004·Drug Metabolism and Pharmacokinetics·Satoshi YamaoriTetsuya Kamataki
Jan 22, 2005·Fundamental & Clinical Pharmacology·Michael Schachter
Jun 13, 2006·Clinical Pharmacology and Therapeutics·Ji-Young ParkJae-Gook Shin
Dec 21, 2006·Clinical Pharmacology and Therapeutics·Kyoung-Ah KimJi-Young Park
Dec 29, 2006·Journal of Clinical Pharmacology·Kyoung-Ah KimJi-Young Park
Mar 3, 2007·Clinical Pharmacology and Therapeutics·F JosephsonL Bertilsson

❮ Previous
Next ❯

Citations

Aug 28, 2012·European Journal of Clinical Pharmacology·Renli TengKathleen A Butler
Jan 15, 2013·Drug Metabolism and Drug Interactions·Joseph Paul KitzmillerWolfgang Sadee
May 9, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·William J CanestaroKenneth E Thummel
Jun 18, 2009·Pharmacogenomics·Maria Alice Vieira WillrichRosario Dominguez Crespo Hirata
Oct 17, 2014·BMC Cancer·Albert BraeuningMichael Schwarz
Sep 1, 2011·Expert Review of Cardiovascular Therapy·Isabell BernlochnerDirk Sibbing
Jun 11, 2015·Expert Opinion on Drug Metabolism & Toxicology·Takeshi Hirota, Ichiro Ieiri
Oct 26, 2010·Clinical Toxicology : the Official Journal of the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists·Virginie MontielPhilippe Hantson
Oct 28, 2014·The FEBS Journal·Swagatika SahooInes Thiele
Apr 20, 2011·British Journal of Clinical Pharmacology·Patrick ReddyKevin Browne
Aug 22, 2015·Clinical Drug Investigation·Kan-kan Wei, Li-rong Zhang
Mar 3, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Cheng-Xian GuoHong-Hao Zhou
Jun 19, 2015·Pharmacogenomics·Nikica Mirošević SkvrceNada Božina
Apr 8, 2015·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·P C OrsolinJ C Nepomuceno
May 20, 2016·Journal of Clinical Pharmacology·Neville F Ford
Apr 24, 2018·Clinical Pharmacology in Drug Development·William McKeandAlain Patat
Mar 9, 2010·Circulation. Cardiovascular Genetics·Kristian M BaileyUNKNOWN SPACE ROCKET Trial Group
Sep 15, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shu YangZhigang Zhao
Sep 18, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keiko MaekawaYoshiro Saito
Jun 17, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diana M FeidtUlrich M Zanger
Nov 23, 2011·Pharmacological Reviews·Patrizia GazzerroMaurizio Bifulco
Aug 10, 2017·Expert Opinion on Drug Metabolism & Toxicology·Elliot Berinstein, Andrew Levy
Dec 22, 2019·Journal of Clinical Medicine·Richard Myles Turner, Munir Pirmohamed
Mar 13, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N R Srinivas
Sep 5, 2020·International Journal of Molecular Sciences·Rossana RoncatoGiuseppe Toffoli
Feb 11, 2021·Personalized Medicine·Brian TomlinsonChristopher Wk Lam

❮ 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.