{"doi":"10.1007/s00044-025-03477-3","title":"Increased plasma concentrations of 6-oxo-methylphenidate in CES1 G134E carriers following a single oral dose of methylphenidate","abstract":null,"journal":"Medicinal Chemistry Research","year":2025,"id":609107,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1565402,"name":"Philip W. Melchert","orcid":null,"position":1,"is_corresponding":false},{"id":1365466,"name":"Ahmed Awad","orcid":"0000-0001-5904-7143","position":2,"is_corresponding":false},{"id":279431,"name":"Christopher R. McCurdy","orcid":"0000-0001-8695-2915","position":3,"is_corresponding":false},{"id":1262084,"name":"Beth Krone","orcid":"0000-0003-4046-8305","position":4,"is_corresponding":false},{"id":1565403,"name":"Jeffrey Newcorn","orcid":null,"position":5,"is_corresponding":false},{"id":525115,"name":"Tanya E. Froehlich","orcid":"0000-0002-4471-289X","position":6,"is_corresponding":false},{"id":819990,"name":"Mark A. Stein","orcid":"0000-0002-4475-8871","position":7,"is_corresponding":false},{"id":1565404,"name":"Josephine Raeuscher","orcid":null,"position":8,"is_corresponding":false},{"id":1565405,"name":"Hao-Jie Zhu","orcid":null,"position":9,"is_corresponding":false},{"id":1247374,"name":"John S. Markowitz","orcid":"0000-0002-9830-5392","position":10,"is_corresponding":false},{"id":1158925,"name":"Qingchen Zhang","orcid":"0000-0001-5525-687X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Increased plasma concentrations of 6-oxo-methylphenidate in CES1 G134E carriers following a single oral dose of methylphenidate","abstract":"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 <i>in vitro</i> 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 <i>in vitro</i> 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.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41567292","pmcid":"PMC12818952","openalex_id":null,"authors":[],"funders":[{"funder_name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","grant_id":"R01 HD093612","title":null}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"https://www.springernature.com/gp/researchers/text-and-data-mining","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12818952/","host_type":"repository"},{"url":"https://link.springer.com/content/pdf/10.1007/s00044-025-03477-3.pdf","host_type":"publisher"},{"url":"https://link.springer.com/article/10.1007/s00044-025-03477-3/fulltext.html","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":[],"keywords":["Pharmacokinetics","ADHD","Methylphenidate","6-Oxo-methylphenidate","Ces1 G143e"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refsnp"},{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-31T03:18:22.334097Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}