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

Abstract

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.

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

“…For TDM of methylphenidate, sampling of plasma at 1-2 h after immediate release or between 5 and 8 h for extended-release formulations are recommended [19]. Stage et al [30] suggested the ritalinic acid/methylphenidate metabolic ratio based on a singlepoint measurement, 3 h after dose (10 mg, Ritalin®) as a marker of CES1 activity. The time point was chosen because of a high correlation with the corresponding AUC ratios (r ≥ 0.90) from 3 h and onwards.…”

“…Sampling closer to dosing may also be more convenient for the patients. The agreement between the two methods (AUC ratios and single-point measurements of metabolite/parent drug) needs to be further studied to assess which ratios and what timepoints would be most relevant for prediction of CES1 activity [30].…”

Review and Consensus on Pharmacogenomic Testing in Psychiatry

“…In contrast, PMs are more likely to experience improvement in ADHD symptoms, but due to their absence of CYP2D6 metabolic activity, they are at also at increased risk of having side effects from atomoxetine and may therefore require lower doses. From a pharmacodynamic perspective, there are a number of interesting findings warranting further investigation related to dopamine and norepinephrine disposition in the brain (e. g., COMT), as well as the contribution of genetic variability in CES1 (carboxylesterase 1) to methylphenidate metabolism [55]. However, the clinical efficacy and utility of testing for these genes remains unknown.…”

Stability of Methylphenidate under Various pH Conditions in the Presence or Absence of Gut Microbiota

“…Genetic variations in CES1, the gene encoding for the CES1 enzyme in the liver, have been shown to impact the enzyme activity towards different substrates in vitro [ 9 ], which could account for differences in MPH hydrolysis among patients. Nevertheless, very little is known about the stability of the drug and whether this could contribute to its low bioavailability in the gut [ 10 , 11 ]. Only recently, the absorption of MPH was modelled based on physicochemical properties of the drug, formulation-related information, and differences in gut physiology along the gastrointestinal tract [ 12 ].…”