title: The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects.
abstract: 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.
  
  
  
  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.
  
  
  
  Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1h-1, range 38.6-93.9) than in the control group (21.4 ng ml-1h-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-1h-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-1h-1, range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1.
  
  
  
  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.affiliation: Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Stage
authors.affiliation: Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Gesche
authors.initials: G
authors.lastname: Jürgens
authors.affiliation: Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.
authors.forename: Louise Schow
authors.initials: LS
authors.lastname: Guski
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ragnar
authors.initials: R
authors.lastname: Thomsen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Bjerre
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferrero-Miliani
authors.affiliation: Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark.
authors.forename: Yassine Kamal
authors.initials: YK
authors.lastname: Lyauk
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Henrik Berg
authors.initials: HB
authors.lastname: Rasmussen
authors.affiliation: Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Dalhoff
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D056915:DNA Copy Number Variations; D003718:Denmark; D005260:Female; D020440:Gene Duplication; D005838:Genotype; D064368:Healthy Volunteers; D006579:Heterozygote; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human
keywords: carboxylesterase 1; methylphenidate; personalized medicine; pharmacogenetics