Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Published

Journal Article

© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics 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.

Full Text

Duke Authors

Cited Authors

  • Kaddurah-Daouk, R; Hankemeier, T; Scholl, EH; Baillie, R; Harms, A; Stage, C; Dalhoff, KP; J┼▒rgens, G; Taboureau, O; Nzabonimpa, GS; Motsinger-Reif, AA; Thomsen, R; Linnet, K; Rasmussen, HB

Published Date

  • August 1, 2018

Published In

Volume / Issue

  • 7 / 8

Start / End Page

  • 525 - 533

Electronic International Standard Serial Number (EISSN)

  • 2163-8306

Digital Object Identifier (DOI)

  • 10.1002/psp4.12309

Citation Source

  • Scopus