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

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.

Keywords: carboxylesterase 1; methylphenidate; personalized medicine; pharmacogenetics.

Figure 1

CES1 gene loci on chromosome 16 spanning about 30 kbp. The four major CES1 haplotypes are designated (A–D). The vertical lines represent the exons of which there are 14. Light and dark green colours indicate regions derived from the original CES1A1 and the pseudogene, CES1P1, respectively

Figure 2

Median concentrations of d‐methylphenidate in relation to CES1 genotype. Sampling times deviating more than 20% from the schedule are not included in the figure (one plasma sample). Control, two copies of wild‐type CES1; 4 copies, four copies of CES1; G143E, subjects carrying the 143E allele of CES1; 3 copies active, three copies of CES1 in which CES1A2 has increased transcriptional activity; CES1A1c, subjects carrying the CES1A1c variant; 3 copies normal, three copies of CES1, in which CES1A2 possesses the common promoter