Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

CPT: Pharmacometrics & Systems Pharmacology
Rima Kaddurah-DaoukPharmacometabolomics Research Network

Abstract

Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half-maximal inhibitory concentration (IC50 ) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme.

References

Oct 21, 1988·JAMA : the Journal of the American Medical Association·D J Safer, J M Krager
Aug 1, 1997·Biological & Pharmaceutical Bulletin·S TakaiK Hirano
Apr 15, 2004·The Journal of Pharmacology and Experimental Therapeutics·Zejin SunWilliam F Bosron
Aug 6, 2005·Journal of Molecular Biology·Christopher D FlemingMatthew R Redinbo
Sep 12, 2006·Journal of Molecular Biology·Sompop BencharitMatthew R Redinbo
Feb 9, 2007·Expert Review of Neurotherapeutics·Mohammad Reza Mohammadi, Shahin Akhondzadeh
Nov 16, 2007·Pharmacology & Therapeutics·Magnus Ingelman-SundbergCristina Rodriguez-Antona
Mar 11, 2008·Biochemical and Biophysical Research Communications·Mika YoshimuraMasaaki Muramatsu
Sep 17, 2008·Pharmacogenetics and Genomics·Tatsuki FukamiTsuyoshi Yokoi
Sep 26, 2008·BMJ : British Medical Journal·Tim KendallUNKNOWN Guideline Development Group
May 7, 2010·Metabolomics : Official Journal of the Metabolomic Society·Rima Kaddurah-DaoukRonald M Krauss
Jul 27, 2010·British Journal of Clinical Pharmacology·Kimie SaiHaruhiro Okuda
Mar 27, 2012·Metabolomics : Official Journal of the Metabolomic Society·Marek J NogaThomas Hankemeier
Jul 19, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ariel D QuirogaRichard Lehner
Nov 13, 2012·PloS One·Ariel D QuirogaRichard Lehner
Mar 29, 2013·PloS One·William R WikoffUNKNOWN Pharmacometabolomics Research Network
Oct 22, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ragnar ThomsenUNKNOWN INDICES Consortium
May 27, 2014·Expert Opinion on Drug Metabolism & Toxicology·Jan FrölichAnja Görtz-Dorten
Jan 1, 2010·Journal of Pesticide Science·Matthew K RossKatye L Herring
Sep 25, 2014·Archives of Toxicology·Ahmed A El-Sherbeni, Ayman O S El-Kadi
Apr 22, 2015·Pharmacogenomics·Henrik Berg RasmussenUNKNOWN INDICES Consortium
Jan 16, 2016·Advances in Clinical and Experimental Medicine : Official Organ Wroclaw Medical University·Anna Wiktorowska-OwczarekJerzy Z Nowak
Feb 13, 2016·Pharmacogenetics and Genomics·Jonathan C SanfordWolfgang Sadee
May 27, 2016·Basic & Clinical Pharmacology & Toxicology·Jian ShiHao-Jie Zhu
Jun 21, 2016·Cell Metabolism·Annika WahlströmFredrik Bäckhed
Jul 9, 2016·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Andrea GaedigkJ Steven Leeder
Jan 15, 2017·British Journal of Clinical Pharmacology·Claus StageUNKNOWN INDICES Consortium

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Citations

Jan 21, 2020·Expert Review of Clinical Pharmacology·Michele MussapVassilios Fanos
Apr 2, 2020·Metabolites·Richard D BegerRima Kaddurah-Daouk
Dec 25, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Lucy Her, Hao-Jie Zhu
Aug 1, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eliane BriandOlivier Taboureau

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Methods Mentioned

BETA
genotyping
X‐ray

Software Mentioned

CLC Drug Discovery Workbench (
GraphPad
Molecular Operating Environment
R
Prism
CLC Drug Discovery Workbench

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