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<p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with methylphenidate used as a first-line treatment. Methylphenidate is primarily hydrolyzed by carboxylesterase 1 (CES1) to inactive ritalinic acid, with minor oxidative metabolism producing active p-OH-methylphenidate and 6-oxo-methylphenidate lactam. The functional single-nucleotide polymorphism (SNP) in <i>CES1</i>, resulting in a glycine (G) to glutamic acid (E) substitution at 143 (<i>G143E</i>), is reported to significantly impair CES1 activity. However, limited clinical research has explored the pharmacokinetics of methylphenidate and its oxidation metabolites in ADHD therapeutics in <i>G143E</i> carriers. Three <i>G143E</i> ADHD subjects were genotyped for the <i>G143E</i> variant, and four non-carriers were identified and enrolled in the pharmacokinetic study. Participants received a single oral dose of methylphenidate, and plasma concentrations of methylphenidate, 6-oxo-methylphenidate, and p-OH-methylphenidate were extracted and quantified. Pharmacokinetic data were analyzed, and in vitro incubation of 6-oxo-methylphenidate with <i>G143E</i> S9 has been conducted. No significant differences were observed in the pharmacokinetics of methylphenidate. <i>CES1 G143E</i> carriers exhibited significantly elevated plasma concentrations of 6-oxo-methylphenidate, with a higher peak plasma concentration (C<sub>max</sub>), area under the curve from time zero to infinity (AUC<sub>0→∞</sub>), and longer half-life (T<sub>1/2</sub>). Reduced function in in vitro studies suggested the impaired CES-mediated biotransformation of 6-oxo-methyphnidate to 6-oxo-ritalinic acid. These results provide pilot data on the substrate-dependent impact of the <i>CES1 G143E</i> variant. Whether or not the elevated concentrations of 6-oxo-methyphenidate contribute to the clinical activity of methylphenidate treatment remains a matter of speculation. Registry: ClinicalTrials.gov, TRN: NCT03781752, Registration date: 4-March-2018.</p><p></p>

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Increased plasma concentrations of 6-oxo-methylphenidate in CES1 G134E carriers following a single oral dose of methylphenidate

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Qingchen Zhang,
  • Philip W. Melchert,
  • Ahmed Awad,
  • Christopher R. McCurdy,
  • Beth Krone,
  • Jeffrey Newcorn,
  • Tanya E. Froehlich,
  • Mark A. Stein,
  • Josephine Raeuscher,
  • Hao-Jie Zhu,
  • John S. Markowitz

摘要

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with methylphenidate used as a first-line treatment. Methylphenidate is primarily hydrolyzed by carboxylesterase 1 (CES1) to inactive ritalinic acid, with minor oxidative metabolism producing active p-OH-methylphenidate and 6-oxo-methylphenidate lactam. The functional single-nucleotide polymorphism (SNP) in CES1, resulting in a glycine (G) to glutamic acid (E) substitution at 143 (G143E), is reported to significantly impair CES1 activity. However, limited clinical research has explored the pharmacokinetics of methylphenidate and its oxidation metabolites in ADHD therapeutics in G143E carriers. Three G143E ADHD subjects were genotyped for the G143E variant, and four non-carriers were identified and enrolled in the pharmacokinetic study. Participants received a single oral dose of methylphenidate, and plasma concentrations of methylphenidate, 6-oxo-methylphenidate, and p-OH-methylphenidate were extracted and quantified. Pharmacokinetic data were analyzed, and in vitro incubation of 6-oxo-methylphenidate with G143E S9 has been conducted. No significant differences were observed in the pharmacokinetics of methylphenidate. CES1 G143E carriers exhibited significantly elevated plasma concentrations of 6-oxo-methylphenidate, with a higher peak plasma concentration (Cmax), area under the curve from time zero to infinity (AUC0→∞), and longer half-life (T1/2). Reduced function in in vitro studies suggested the impaired CES-mediated biotransformation of 6-oxo-methyphnidate to 6-oxo-ritalinic acid. These results provide pilot data on the substrate-dependent impact of the CES1 G143E variant. Whether or not the elevated concentrations of 6-oxo-methyphenidate contribute to the clinical activity of methylphenidate treatment remains a matter of speculation. Registry: ClinicalTrials.gov, TRN: NCT03781752, Registration date: 4-March-2018.