The impact of <i>CES1</i> genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects

Stage, Claus; Jürgens, Gesche; Guski, Louise Schow; Thomsen, Ragnar; Bjerre, Ditte; Ferrero-Miliani, Laura; Lyauk, Yassine Kamal; Rasmussen, Henrik Berg; Dalhoff, Kim

doi:10.1111/bcp.13237

Cited by 36 publications

(50 citation statements)

References 31 publications

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“…In terms of the CES1 143E allele, we found no pharmacokinetic impact on the metabolism of enalapril. This is in contrast to our MPH study, in which a markedly (149%) and highly significant increase in d ‐MPH AUC was found compared to the control group indicating decreased metabolizing capacity . In a recent human study, Tarkiainen et al .…”

Section: Discussioncontrasting

confidence: 99%

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

Stage

Jürgens

Guski

et al. 2017

Basic Clin Pharma Tox

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This study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time-points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: group 1 (control group, n = 16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n = 5) with four copies of CES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring the CES1A1c variant; and group 6 (n = 10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 ng/ml x h in the control group versus 310, 282, 294, 344 and 306 ng/ml x h in groups 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.

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Section: Discussioncontrasting

confidence: 99%

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

Stage

Jürgens

Guski

et al. 2017

Basic Clin Pharma Tox

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“…All volunteers were informed about trial objectives and potential risks prior to their participation, and an informed consent form was signed by each subject. Detailed inclusion criteria have been described elsewhere . The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies …”

Section: Methodsmentioning

confidence: 99%

“…Lower limit of quantification was 0.205 ng/mL for the MPH isomers and 2.05 ng/mL for the RA isomers. The procedure has been described more detailed elsewhere …”

Section: Methodsmentioning

confidence: 99%

“…Metabolic ratios based on single‐point measurements are widely used in clinical pharmacological research, providing a practical and inexpensive alternative to full AUC analyses. We have previously investigated the impact of CES1 variations on the metabolism of MPH using a full‐scale pharmacokinetic profile including AUC . Using a 3‐hours d ‐RA/ d ‐MPH metabolic ratio (MR), the purpose of the present study was to examine the impact on MPH metabolism of CES1 SNPs, which have not been functionally characterised yet.…”

Section: Introductionmentioning

confidence: 99%

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The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios

Stage

Dalhoff

Rasmussen

et al. 2019

Basic Clin Pharma Tox

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The present clinical trial investigated the impact of selected SNPs in CES1 on the metabolic activity of the enzyme. For this purpose, we used methylphenidate (MPH) as a pharmacological probe and the d‐RA/d‐MPH (metabolite/parent drug) ratios as a measure of enzymatic activity. This metabolic ratio (MR) was validated against the AUC ratios (AUCd‐RA/AUCd‐MPH). CES1 SNPs from 120 volunteers were identified, and 12 SNPs fulfilling predefined inclusion criteria were analysed separately, comparing the effect of each genotype on the metabolic ratios. The SNP criteria were as follows: presence of Hardy‐Weinberg equilibrium, a minor allele frequency ≥ 0.01 and a clearly interpretable sequencing result in at least 30% of the individuals. Each participant ingested 10 mg of racemic methylphenidate, and blood samples were drawn prior to and 3 hours after drug administration. The SNP analysis confirmed the considerable impact of rs71647871 (G143E) in exon 4 on drug metabolism. In addition, three volunteers with markedly lower median MR, indicating decreased CES1 activity, harboured the same combination of three SNPs in intron 5. The median MR for these SNPs was 8.2 for the minor allele compared to 16.4 for the major alleles (P = 0.04). Hence, one of these or the combination of these SNPs could be of clinical significance considering that the median MR of the G143E group was 5.4. The precise genetic relationship of this finding is currently unknown, as is the clinical significance.

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“…On testing correlations between CES1 genotype and PK, significance was mostly seen in the comparison between the normal genotype (group 1) and the group with the rs71647871 143E allele ( n = 6) with a higher AUC of d‐MPH, half‐life of d‐MPH, and C max of d‐MPH in the latter of these two groups ( Table ). Detailed analysis of the genotype/PK comparisons shown in Table have been previously reported using a slightly different statistical approach, which involved application of the Kruskal‐Wallis test …”

Section: Resultsmentioning

confidence: 99%

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

Kaddurah‐Daouk

Hankemeier

Scholl

et al. 2018

CPT Pharmacom & Syst Pharma

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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 (IC50) 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.

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

Abstract: 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.

Cited by 36 publications

References 31 publications

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate

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