Initial Evidence of CES1 Gene Variants Influencing the Pharmacokinetics and Clinical Effects of Methylphenidate

Introduction: Methylphenidate (MPH) is the first-line medication for treating attention-deficit/hyperactivity disorder (ADHD). The enzyme carboxylesterase 1 plays a key role in metabolizing MPH into the inactive metabolite ritalinic acid (RA). Clinically, ADHD patients show a variable response to MPH, which may be influenced by differences in first-pass metabolism and genetic factors. The aim of this study was to investigate the impact of CES1 gene variants on pharmacokinetic and pharmacodynamic parameters in children and adolescents with ADHD undergoing MPH treatment.

Methods: In a prospective study conducted at the University Hospital of Wuerzburg (ethics approval 25-21am), children and adolescents with ADHD were treated with MPH according to clinical guidelines and assessed for neurocognitive correlates. After eight weeks, blood samples were collected to analyze single nucleotide polymorphisms (SNPs) and measure serum levels of MPH and RA. Pharmacokinetic parameters, including the metabolite-to-parent ratio (MPR) and dose-corrected concentration (CD), as well as pharmacodynamic parameters, such as disease severity, the efficacy of MPH therapy according to the Clinical Global Impression (CGI), and adverse drug reactions (ADRs), were analyzed using linear regression while controlling for age, sex, weight, and genetic variants.

Results: Among 28 patients (19 male, 9 female; mean age: 11.15 ± 3.17 years), significant associations were found between certain SNPs and pharmacokinetic parameters. One SNP was significantly correlated with MPR (rs28709456, p ≤ 0.002), and another SNP with CDRS (rs3217164, p = 0.0125). Pharmacodynamic analyses revealed associations between specific SNPs and disease severity (rs11076120, p = 0.017) as well as between ADRs, such as sleep disturbances (16:55854877, p = 0.049), loss of appetite (16:55846761, p = 0.046), irritability (16:55867006, p = 0.039; rs3217164, p = 0.03), and sadness (rs2002577, p ≤ 0.001; rs2244613, p ≤ 0.001).

Conclusion: These findings suggest that specific CES1 SNPs may influence MPH metabolism and the occurrence of ADRs. Further validation in a larger sample is needed to support the future individualization of MPH dosing and improve medication safety for patients with ADHD.

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Artikel online veröffentlicht:
30. April 2025