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Evaluation of Brain Anticholinergic Activities of Urinary Spasmolytic Drugs Using a High-Throughput Radio Receptor Bioassay

Authors

  • Stine Mjåvatn Jakobsen MSc Pharm,

    1. From the *Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Geriatric medicine, Oslo University Hospital, Ullevaal, Oslo, Norway; Pharmaceutical services, The Hospital Pharmacies, Oslo, Norway; and §Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
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  • Hege Kersten MSc Pharm,

    1. From the *Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Geriatric medicine, Oslo University Hospital, Ullevaal, Oslo, Norway; Pharmaceutical services, The Hospital Pharmacies, Oslo, Norway; and §Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
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  • Espen Molden PhD

    1. From the *Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Geriatric medicine, Oslo University Hospital, Ullevaal, Oslo, Norway; Pharmaceutical services, The Hospital Pharmacies, Oslo, Norway; and §Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
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Address correspondence to Espen Molden, Department of Pharmaceutical Biosciences, School of Pharmacy, Postbox 1068 Blindern, 0316 Oslo, Norway. E-mail: espen.molden@farmasi.uio.no

Abstract

OBJECTIVES: To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs).

DESIGN: In vitro study.

SETTING: Laboratory.

PARTICIPANTS: None.

MEASUREMENTS: A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA).

RESULTS: 5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (<one-third the AA of oxybutynin and solifenacin).

CONCLUSION: Tolterodine and fesoterodine appear to have the highest pharmacodynamic potential to induce central anticholinergic side effects of the tested USDs. Darifenacin displayed the lowest AA, and combined with a low degree of brain distribution, it has probably the most favorable pharmacological profile of the USDs with respect to risk of cognitive impairment in older adults.

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