TY - JOUR

T1 - The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects

AU - Stage, Claus

AU - Jürgens, Gesche

AU - Guski, Louise Schow

AU - Thomsen, Ragnar

AU - Bjerre, Ditte

AU - Ferrero-Miliani, Laura

AU - Lyauk, Yassine Kamal

AU - Berg Rasmussen, Henrik

AU - Dalhoff, Kim

AU - INDICES Consortium

N1 - This article is protected by copyright. All rights reserved.

PY - 2017/7

Y1 - 2017/7

N2 - AIM: This study investigated the influence of CES1 variations, including the 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 x h, range 38.6-93.9) than in the control group (21.4 ng/ml x h, 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 x h, range 21.3-62.8) than in the control group (p = 0.01) and the group with three CES1 copies (23.8 ng/ml x h, 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.

AB - AIM: This study investigated the influence of CES1 variations, including the 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 x h, range 38.6-93.9) than in the control group (21.4 ng/ml x h, 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 x h, range 21.3-62.8) than in the control group (p = 0.01) and the group with three CES1 copies (23.8 ng/ml x h, 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.

U2 - 10.1111/bcp.13237

DO - 10.1111/bcp.13237

M3 - Journal article

C2 - 28087982

VL - 83

SP - 1506

EP - 1514

JO - British Journal of Clinical Pharmacology, Supplement

JF - British Journal of Clinical Pharmacology, Supplement

SN - 0264-3774

IS - 7

ER -