Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Rima Kaddurah-Daouk; Thomas Hankemeier; Elizabeth H. Scholl; Rebecca Baillie; Amy Harms; Claus Stage; Kim P. Dalhoff; Gesche Jűrgens; Olivier  Taboureau; Grace S. Nzabonimpa; Alison A. Motsinger-Reif; Ragnar Thomsen; Kristian Linnet; Henrik B. Rasmussen

doi:10.1002/psp4.12309

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Rima Kaddurah-Daouk, Thomas Hankemeier, Elizabeth H. Scholl, Rebecca Baillie, Amy Harms, Claus Stage, Kim P. Dalhoff, Gesche Jűrgens, Olivier Taboureau, Grace S. Nzabonimpa, Alison A. Motsinger-Reif, Ragnar Thomsen, Kristian Linnet, Henrik B. Rasmussen^*

^*Corresponding author for this work

Department of Biotechnology and Biomedicine

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	C P T: Pharmacometrics & Systems Pharmacology
Volume	7
Issue number	8
Pages (from-to)	525-533
ISSN	2163-8306
DOIs	https://doi.org/10.1002/psp4.12309
Publication status	Published - 2018

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Kaddurah-Daouk, R., Hankemeier, T., Scholl, E. H., Baillie, R., Harms, A., Stage, C., Dalhoff, K. P., Jűrgens, G., Taboureau, O., Nzabonimpa, G. S., Motsinger-Reif, A. A., Thomsen, R., Linnet, K., & Rasmussen, H. B. (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

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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 = 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.",

author = "Rima Kaddurah-Daouk and Thomas Hankemeier and Scholl, {Elizabeth H.} and Rebecca Baillie and Amy Harms and Claus Stage and Dalhoff, {Kim P.} and Gesche J{\H u}rgens and Olivier Taboureau and Nzabonimpa, {Grace S.} and Motsinger-Reif, {Alison A.} and Ragnar Thomsen and Kristian Linnet and Rasmussen, {Henrik B.}",

note = "This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License",

year = "2018",

doi = "10.1002/psp4.12309",

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Kaddurah-Daouk, R, Hankemeier, T, Scholl, EH, Baillie, R, Harms, A, Stage, C, Dalhoff, KP, Jűrgens, G, Taboureau, O, Nzabonimpa, GS, Motsinger-Reif, AA, Thomsen, R, Linnet, K & Rasmussen, HB 2018, 'Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate', C P T: Pharmacometrics & Systems Pharmacology, vol. 7, no. 8, pp. 525-533. https://doi.org/10.1002/psp4.12309

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 P.

AU - Jűrgens, Gesche

AU - Taboureau, Olivier

AU - Nzabonimpa, Grace S.

AU - Motsinger-Reif, Alison A.

AU - Thomsen, Ragnar

AU - Linnet, Kristian

AU - Rasmussen, Henrik B.

N1 - This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License

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 = 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.

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 = 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.

U2 - 10.1002/psp4.12309

DO - 10.1002/psp4.12309

M3 - Journal article

C2 - 30169917

SN - 2163-8306

VL - 7

SP - 525

EP - 533

JO - C P T: Pharmacometrics & Systems Pharmacology

JF - C P T: Pharmacometrics & Systems Pharmacology

IS - 8

ER -

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

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