ArticleJournal of pharmaceutical sciences2022
Physiologically-Based Pharmacokinetic Modeling to Predict Methylphenidate Exposure Affected by Interplay Among Carboxylesterase 1 Pharmacogenetics, Drug-Drug Interactions, and Sex.
Article in Journal of pharmaceutical sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 7 citations in OpenAlex.
- Evaluating plasma carboxylesterase 1 as a protein biomarker for pharmacokinetics and metabolic dysfunction-associated steatotic liver disease.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Sex differences in the response to treatment of attention deficit hyperactivity disorder.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- An open-source framework for physiologically-based pharmacokinetic modeling of kinetics in the female reproductive tract.Frontiers in pharmacology · 2026Article
- Physiologically-Based Pharmacokinetic Modeling of the PARP Inhibitor Niraparib.CPT: pharmacometrics & systems pharmacology · 2026Article
- Increased Plasma Concentrations of 6-oxo-Methylphenidate inMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2025Article
- Methylphenidate and Its Impact on Redox Balance and Behavior.Journal of xenobiotics · 2025Review
- Carboxylesterase Factors Influencing the Therapeutic Activity of Common Antiviral Medications Used for SARS-CoV-2 Infection.Pharmaceutics · 2025Review
- Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review.Expert opinion on drug metabolism & toxicology · 2024Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
objectiveThe pharmacokinetics (PK) of methylphenidate (MPH) differ significantly among individuals. Carboxylesterase 1 (CES1) is the primary enzyme metabolizing MPH, and its function is affected by genetic variants, drug-drug interaction (DDI), and sex. The object of this study is to evaluate CES1 pharmacogenetics as related to MPH metabolism using human liver samples and develop a physiologically-based pharmacokinetic (PBPK) modeling approach to investigate the influence of CES1 genotypes and other factors on MPH PK.
methodsThe effect of the CES1 variant G143E (rs71647871) on MPH metabolism was studied utilizing 102 individual human liver S9 (HLS9) fraction samples. PBPK models were developed using the population-based PBPK software PK-Sim® by incorporating the HLS9 incubation data. The established models were applied to simulate MPH PK profiles under various clinical scenarios, including different genotypes, drug-alcohol interactions, and the difference between males and females.
resultsThe HLS9 incubation study showed that subjects heterozygous for the CES1 variant G143E metabolized MPH at a rate of approximately 50% of that in non-carriers. The developed PBPK models successfully predicted the exposure alteration of MPH from the G143E genetic variant, ethanol-MPH DDI, and sex. Importantly, the study suggests that male G143E carriers who are alcohol consumers are at a higher risk of MPH overexposure.
conclusionPBPK modeling provides a means for better understanding the mechanisms underlying interindividual variability in MPH PK and PD and could be utilized to develop a safer and more effective MPH pharmacotherapy regimen.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.