Therapeutic Drug Monitoring of Rivastigmine and Donepezil Under Consideration of CYP2D6 Genotype-Dependent Metabolism of Donepezil
| Autor: | Timo Grimmer, Marion Ortner, Katharina Buerger, Claudia Müller, Heike Schneider, Janine Diehl-Schmid, Marion Stange, Werner Steimer, Felix Müller-Sarnowski, Hans Förstl, Charlotte Schröder |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug CYP2D6 Aché media_common.quotation_subject Pharmaceutical Science Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine mental disorders Drug Discovery medicine Donepezil media_common Rivastigmine medicine.diagnostic_test biology business.industry Cytochrome P450 Acetylcholinesterase language.human_language 030104 developmental biology chemistry Therapeutic drug monitoring 030220 oncology & carcinogenesis biology.protein language business medicine.drug |
| Zdroj: | Drug Design, Development and Therapy. 14:3251-3262 |
| ISSN: | 1177-8881 |
| DOI: | 10.2147/dddt.s247259 |
| Popis: | Background The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil. CYP2D6 polymorphisms can cause altered enzyme activity resulting in lower or higher than expected drug concentrations of donepezil. Objective We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of CYP 2D6 genotype or gene dose-dependent metabolism of donepezil. Methods Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography - tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess CYP2D6 genotype and gene dose. Results Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (β=0.465; p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on CYP2D6 gene dose. Conclusion Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from CYP2D6 genotyping or treatment with an AChE-I independent of CYP metabolism. |
| Databáze: | OpenAIRE |
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