Claus Stage1, Gesche Jürgens2, Louise Schow Guski1, Ragnar Thomsen3, Ditte Bjerre4, Laura Ferrero-Miliani4, Yassine Kamal Lyauk2, Henrik Berg Rasmussen4, Kim Dalhoff1. 1. Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark. 2. Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark. 3. Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Copenhagen, Denmark.
Abstract
AIMS: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate. METHODS: CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points. RESULTS: Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1 h-1 , range 38.6-93.9) than in the control group (21.4 ng ml-1 h-1 , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml-1 h-1 , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml-1 h-1 , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1. CONCLUSIONS: The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme.
AIMS: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate. METHODS:CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points. RESULTS: Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1 h-1 , range 38.6-93.9) than in the control group (21.4 ng ml-1 h-1 , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml-1 h-1 , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml-1 h-1 , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1. CONCLUSIONS: The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme.
Authors: S Yamada; K Richardson; M Tang; J Halaschek-Wiener; V J Cook; J M Fitzgerald; K Elwood; F Marra; A Brooks-Wilson Journal: Pharmacogenomics J Date: 2010-03-02 Impact factor: 3.550
Authors: Martin H Teicher; Ann Polcari; Mary Foley; Elizabeth Valente; Cynthia E McGreenery; Wei-Wei Chang; Gordon McKay; Kamal K Midha Journal: J Child Adolesc Psychopharmacol Date: 2006-08 Impact factor: 2.576
Authors: Hao-Jie Zhu; Kennerly S Patrick; Hong-Jie Yuan; Jun-Sheng Wang; Jennifer L Donovan; C Lindsay DeVane; Robert Malcolm; Julie A Johnson; Geri L Youngblood; Douglas H Sweet; Taimour Y Langaee; John S Markowitz Journal: Am J Hum Genet Date: 2008-05-15 Impact factor: 11.025
Authors: Jan Buitelaar; Sven Bölte; Daniel Brandeis; Arthur Caye; Nina Christmann; Samuele Cortese; David Coghill; Stephen V Faraone; Barbara Franke; Markus Gleitz; Corina U Greven; Sandra Kooij; Douglas Teixeira Leffa; Nanda Rommelse; Jeffrey H Newcorn; Guilherme V Polanczyk; Luis Augusto Rohde; Emily Simonoff; Mark Stein; Benedetto Vitiello; Yanki Yazgan; Michael Roesler; Manfred Doepfner; Tobias Banaschewski Journal: Front Behav Neurosci Date: 2022-07-06 Impact factor: 3.617
Authors: 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 Journal: CPT Pharmacometrics Syst Pharmacol Date: 2018-08