Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.

Published

Journal Article

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; INDICES Consortium, ; Pharmacometabolomics Research Network,

Published Date

  • August 2018

Published In

Volume / Issue

  • 7 / 8

Start / End Page

  • 525 - 533

PubMed ID

  • 30169917

Pubmed Central ID

  • 30169917

Electronic International Standard Serial Number (EISSN)

  • 2163-8306

Digital Object Identifier (DOI)

  • 10.1002/psp4.12309

Language

  • eng

Conference Location

  • United States