AI Article Synopsis
- Methylphenidate (MPH) is commonly prescribed for attention-deficit/hyperactivity disorder, but some patients require unusually high doses, possibly due to genetic differences affecting drug metabolism.
- A study involving three patients taking doses between 180 to 640 mg of MPH found that their plasma concentrations were lower than expected, indicating a faster metabolism of the drug.
- However, genetic testing of the CES1 gene did not reveal any variants that could account for the increased clearance of MPH in these patients, suggesting other factors may be involved in their high dosage needs.
Article Abstract
Purpose/background: Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene.
Methods/procedures: The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction.
Findings/results: Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH.
Implications/conclusions: In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.
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| http://dx.doi.org/10.1097/JCP.0000000000001772 | DOI Listing |
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