PMID: 9549641Apr 29, 1998Paper

Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4

Journal of Clinical Pharmacology
Karthik VenkatakrishnanR I Shader

Abstract

The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no det...Continue Reading

References

Apr 1, 1978·Journal of Pharmacokinetics and Biopharmaceutics·K YamaokaT Uno
Oct 1, 1992·Clinical Pharmacology and Therapeutics·U Breyer-PfaffP Baumann
May 1, 1985·Clinical Pharmacokinetics·P SchulzL Hollister
Apr 1, 1986·Clinical Pharmacology and Therapeutics·B MellströmF Sjöqvist
Sep 1, 1984·Clinical Pharmacology and Therapeutics·N M WoolhouseF Sjöqvist
Oct 1, 1983·Clinical Pharmacology and Therapeutics·B MellströmF Sjöqvist
Feb 22, 1994·Biochemistry·J A GoldsteinB I Ghanayem
Dec 1, 1996·Human & Experimental Toxicology·M Dickins, M K Bayliss
Jan 1, 1997·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·R T CouttsG B Baker
Feb 1, 1997·British Journal of Clinical Pharmacology·P GhahramaniG T Tucker
Feb 4, 1998·Biochemical Pharmacology·L L von MoltkeR I Shader

❮ Previous
Next ❯

Citations

Apr 29, 1998·Journal of Clinical Pharmacology·L L von MoltkeR I Shader
May 13, 2009·Journal of Neural Transmission·Arun K TiwariDaniel J Müller
Jul 8, 2009·Applied Biochemistry and Biotechnology·Sepuri Asha, Maravajhala Vidyavathi
Oct 2, 2012·CNS Drugs·Yumiko AkamineTsukasa Uno
May 14, 2005·Critical Reviews in Oncology/hematology·Peter BlowerMatti Aapro
Mar 1, 2000·Brain Research·P VoirolP Baumann
May 29, 2003·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·A FerrariA Bertolini
Jul 1, 2002·Environmental Toxicology and Pharmacology·Franca M BurattiEmanuela Testai
Jul 20, 2011·Journal of the American Chemical Society·Matthew J TraylorDouglas S Clark
Mar 28, 2008·Journal of the American Chemical Society·Yousong DingDavid H Sherman
Mar 24, 2004·Inflammopharmacology·Costas Ioannides
Feb 28, 2001·Journal of Clinical Pharmacology·L L von MoltkeR I Shader
Oct 5, 2001·Journal of Clinical Pharmacology·K VenkatakrishnanD J Greenblatt
Nov 8, 2001·Journal of Clinical Pharmacology·K VenkatakrishnanD J Greenblatt
Mar 10, 2000·Clinical Pharmacokinetics·K VenkatakrishnanD J Greenblatt
Sep 8, 2000·Clinical Pharmacokinetics·J A Carrillo, J Benitez
Sep 12, 2002·Clinical Pharmacokinetics·Zeruesenay DestaDavid A Flockhart
Oct 13, 2009·Clinical Pharmacokinetics·Shu-Feng Zhou
Feb 5, 2014·Chemical & Pharmaceutical Bulletin·Tamer Zekry AttiaTadayuki Uno
Apr 3, 2014·BMC Evolutionary Biology·Ramatoulie E JanhaRobert T Walton
Dec 3, 2014·Pharmacological Reports : PR·Jacek WójcikowskiWładysława A Daniel
Apr 22, 2014·Journal of Pharmaceutical and Biomedical Analysis·Dany SpaggiariSerge Rudaz
Sep 24, 2015·Expert Review of Neurotherapeutics·Fernando Rico-VillademorosElena P Calandre
Sep 10, 2014·Expert Opinion on Drug Metabolism & Toxicology·Domenico ItalianoJose de Leon
May 23, 2012·Expert Opinion on Drug Metabolism & Toxicology·Roja Rahimi, Mohammad Abdollahi
Jun 12, 2009·Drug Metabolism Reviews·Shu-Feng ZhouBalram Chowbay
Aug 26, 1999·Drug Metabolism Reviews·S Ekins, S A Wrighton
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Aug 6, 2002·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C Ioannides
Nov 23, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·M D LeeL Gong
Mar 2, 2011·The American Journal of Geriatric Pharmacotherapy·Pritish S Pawar, Douglas A Woo
Mar 21, 2008·Psychosomatics·Jessica R OesterheldNeil B Sandson
Jun 11, 2015·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·A S YoussefS Nagar
Apr 26, 2003·Journal of Clinical Pharmacy and Therapeutics·E Tanaka
Jun 6, 2008·Journal of Clinical Pharmacology·J Andrew WilliamsSteven A Wrighton

❮ 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.