Open AccessPharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate
Author(s) -
KaddurahDaouk Rima,
Hankemeier Thomas,
Scholl Elizabeth H.,
Baillie Rebecca,
Harms Amy,
Stage Claus,
Dalhoff Kim P.,
Jűrgens Gesche,
Taboureau Olivier,
Nzabonimpa Grace S.,
MotsingerReif Alison A.,
Thomsen Ragnar,
Linnet Kristian,
Rasmussen Henrik B.
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12309
Subject(s) - methylphenidate , pharmacokinetics , carboxylesterase , phosphatidylcholine , pharmacology , metabolism , in silico , chemistry , enzyme , biochemistry , biology , gene , medicine , phospholipid , attention deficit hyperactivity disorder , psychiatry , membrane
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 (IC 50 ) 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.