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; INDICES Consortium; Pharmacometabolomics Research Network

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, INDICES Consortium, Pharmacometabolomics Research Network

^*Corresponding author for this work

5 Citations (Scopus)

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	CPT: Pharmacometrics and Systems Pharmacology
Volume	7
Issue number	8
Pages (from-to)	525-533
Number of pages	9
ISSN	2163-8306
DOIs	https://doi.org/10.1002/psp4.12309
Publication status	Published - 1 Aug 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., INDICES Consortium, & Pharmacometabolomics Research Network (2018). Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. CPT: Pharmacometrics and Systems Pharmacology, 7(8), 525-533. https://doi.org/10.1002/psp4.12309

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, INDICES Consortium & Pharmacometabolomics Research Network 2018, 'Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate', CPT: Pharmacometrics and Systems Pharmacology, vol. 7, no. 8, pp. 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.} and {INDICES Consortium} and {Pharmacometabolomics Research Network}",

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doi = "10.1002/psp4.12309",

language = "English",

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pages = "525--533",

journal = "C P T: Pharmacometrics & Systems Pharmacology",

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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.

AU - INDICES Consortium

AU - Pharmacometabolomics Research Network

PY - 2018/8/1

Y1 - 2018/8/1

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.

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U2 - 10.1002/psp4.12309

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C2 - 30169917

AN - SCOPUS:85052515415

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JO - C P T: Pharmacometrics & Systems Pharmacology

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ER -

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

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