Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Rima Kaddurah-Daouk, Thomas Hankemeier, Elizabeth H. Scholl, Rebecca Baillie, Amy Harms, Claus Stage, Kim Peder Dalhoff, Gesche Jürgens, Olivier Taboureau, Grace Shema Nzabonimpa, Alison A. Motsinger-Reif, Ragnar Thomsen, Henrik Berg Rasmussen, Kristian Linnet, INDICES Consortium, Pharmacometabolomics Research Network

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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 5 0.001) and a phosphatidylcholine (q value 5 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value 5 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 lM, 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
OriginalsprogEngelsk
TidsskriftC P T: Pharmacometrics & Systems Pharmacology
Vol/bind7
Udgave nummer8
Sider (fra-til)525-533
ISSN2163-8306
DOI
StatusUdgivet - 2018

Citer dette

Kaddurah-Daouk, R., Hankemeier, T., Scholl, E. H., Baillie, R., Harms, A., Stage, C., ... Pharmacometabolomics Research Network (2018). Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. C P T: Pharmacometrics & Systems Pharmacology, 7(8), 525-533. https://doi.org/10.1002/psp4.12309
Kaddurah-Daouk, Rima ; Hankemeier, Thomas ; Scholl, Elizabeth H. ; Baillie, Rebecca ; Harms, Amy ; Stage, Claus ; Dalhoff, Kim Peder ; Jürgens, Gesche ; Taboureau, Olivier ; Nzabonimpa, Grace Shema ; Motsinger-Reif, Alison A. ; Thomsen, Ragnar ; Rasmussen, Henrik Berg ; Linnet, Kristian ; INDICES Consortium ; Pharmacometabolomics Research Network. / Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. I: C P T: Pharmacometrics & Systems Pharmacology. 2018 ; Bind 7, Nr. 8. s. 525-533.
@article{6a4c928a7ca94ff6a97f19bfda2dd6bd,
title = "Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate",
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 5 0.001) and a phosphatidylcholine (q value 5 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value 5 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 lM, 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",
author = "Rima Kaddurah-Daouk and Thomas Hankemeier and Scholl, {Elizabeth H.} and Rebecca Baillie and Amy Harms and Claus Stage and Dalhoff, {Kim Peder} and Gesche J{\"u}rgens and Olivier Taboureau and Nzabonimpa, {Grace Shema} and Motsinger-Reif, {Alison A.} and Ragnar Thomsen and Rasmussen, {Henrik Berg} and Kristian Linnet and {INDICES Consortium} and {Pharmacometabolomics Research Network}",
year = "2018",
doi = "10.1002/psp4.12309",
language = "English",
volume = "7",
pages = "525--533",
journal = "C P T: Pharmacometrics & Systems Pharmacology",
issn = "2163-8306",
publisher = "JohnWiley & Sons, Inc.",
number = "8",

}

Kaddurah-Daouk, R, Hankemeier, T, Scholl, EH, Baillie, R, Harms, A, Stage, C, Dalhoff, KP, Jürgens, G, Taboureau, O, Nzabonimpa, GS, Motsinger-Reif, AA, Thomsen, R, Rasmussen, HB, Linnet, K, INDICES Consortium & Pharmacometabolomics Research Network 2018, 'Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate', C P T: Pharmacometrics & Systems Pharmacology, bind 7, nr. 8, s. 525-533. https://doi.org/10.1002/psp4.12309

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. / Kaddurah-Daouk, Rima; Hankemeier, Thomas; Scholl, Elizabeth H.; Baillie, Rebecca; Harms, Amy; Stage, Claus; Dalhoff, Kim Peder; Jürgens, Gesche; Taboureau, Olivier; Nzabonimpa, Grace Shema; Motsinger-Reif, Alison A.; Thomsen, Ragnar; Rasmussen, Henrik Berg; Linnet, Kristian; INDICES Consortium; Pharmacometabolomics Research Network.

I: C P T: Pharmacometrics & Systems Pharmacology, Bind 7, Nr. 8, 2018, s. 525-533.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

AU - Kaddurah-Daouk, Rima

AU - Hankemeier, Thomas

AU - Scholl, Elizabeth H.

AU - Baillie, Rebecca

AU - Harms, Amy

AU - Stage, Claus

AU - Dalhoff, Kim Peder

AU - Jürgens, Gesche

AU - Taboureau, Olivier

AU - Nzabonimpa, Grace Shema

AU - Motsinger-Reif, Alison A.

AU - Thomsen, Ragnar

AU - Rasmussen, Henrik Berg

AU - Linnet, Kristian

AU - INDICES Consortium

AU - Pharmacometabolomics Research Network

PY - 2018

Y1 - 2018

N2 - 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 5 0.001) and a phosphatidylcholine (q value 5 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value 5 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 lM, 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

AB - 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 5 0.001) and a phosphatidylcholine (q value 5 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value 5 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 lM, 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

U2 - 10.1002/psp4.12309

DO - 10.1002/psp4.12309

M3 - Journal article

VL - 7

SP - 525

EP - 533

JO - C P T: Pharmacometrics & Systems Pharmacology

JF - C P T: Pharmacometrics & Systems Pharmacology

SN - 2163-8306

IS - 8

ER -