Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
E-pub ahead of print

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Oral Immunosuppressive Treatment of Myasthenia Gravis in Denmark: A Nationwide Drug Utilization Study, 1996-2013

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. A Systematic Review on Insulin Overdose Cases: Clinical Course, Complications and Novel Treatment Options

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Emergencies related to recreational drug abuse in Spain compared to emergencies attended in 3 European areas

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Obesity-induced CYP2E1 activity in children

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Sparsom evidens for effekt og sikkerhed af propranolol ved eksamensangst

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Ventrikelaspiration er meget sjældent indiceret ved forgiftninger

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

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: presence of Hardy-Weinberg equilibrium, a minor allele frequency ≥ 0.01, and a clearly interpretable sequencing result in at least 30% of the subjects. Each participant ingested 10 mg of racemic methylphenidate, and blood samples were drawn prior to and 3 hr 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalBasic & clinical pharmacology & toxicology
ISSN1742-7843
DOIs
Publication statusE-pub ahead of print - 24 Feb 2019

ID: 56746152