Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

INDICES Consortium, Pharmacometabolomics Research Network, 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

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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 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

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