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Oxybutynin and trospium are substrates of the human organic cation transporters

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Abstract

The muscarinic antagonists oxybutynin and trospium are used as spasmolytic agents for the treatment of overactive urinary bladder disease. Recently, it has been shown that trospium, but not oxybutynin, is a substrate of the multidrug efflux carrier P-glycoprotein, but carrier-mediated drug uptake has not been directly analysed for both drugs. However, trospium has been previously shown to exhibit inhibitory potency for the organic cation transporters (OCTs). The aim of the present study was to examine whether trospium and oxybutynin are substrates, i.e. are transported by the human OCTs (hOCT1, hOCT2 and hOCT3). Therefore, we measured total and specific (decynium-22-sensitive) uptake, and saturation kinetics of the uptake for [3H]oxybutynin and [3H]trospium in human embryonic kidney (HEK293) cells transiently transfected with the cDNA of hOCT1, hOCT2 or hOCT3. In addition, we determined IC50 values for inhibition of hOCT-mediated [3H]MPP+ uptake by unlabelled trospium and oxybutynin. Total uptake of [3H]oxybutynin was very high in all transfected HEK293 cells and only a small portion was due to specific, decynium-22-sensitive hOCT-mediated uptake. Oxybutynin inhibited [3H]MPP+ uptake by the three hOCTs with IC50 values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at hOCT1 with K m of 8 μM and V max of 484 pmol/mg protein/min. The rank order of affinity (1/IC50 or 1/K m) of specific oxybutynin uptake was hOCT1 > hOCT2 = hOCT3. The observed high non-specific uptake is obviously a consequence of the high lipophilicity of this uncharged drug. Thus, hOCTs may not play a significant role for the overall pharmacokinetics and tissue distribution of oxybutynin. However, and in contrast to oxybutynin, uptake of [3H]trospium, an organic cation, was mainly due to carrier-mediated uptake by the three hOCTs. With IC50 values of 18, 1.4 and 710 μM (at hOCT1, hOCT2 and hOCT3, respectively) and K m values of 17 and 8 μM and about identical V max values of about 90 pmol/mg protein/min at hOCT1 and hOCT2, respectively; the rank order of affinity (1/IC50 or 1/K m) of specific uptake of trospium was hOCT2 > hOCT1 > > hOCT3. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, hOCT1 and hOCT3 may be involved in the tissue uptake of this drug in the urinary bladder.

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Acknowledgement

The study was supported by Dr. R. Pfleger GmbH (Bamberg, Germany) by organising and financing the labelling of both drugs.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Bonn, Biomedical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Birger Wenge & Heinz Bönisch

  2. Institute of Pharmacology and Toxicology, University of Giessen, Giessen, Germany

    Joachim Geyer

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  1. Birger Wenge
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  2. Joachim Geyer
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  3. Heinz Bönisch
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Correspondence to Heinz Bönisch.

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Wenge, B., Geyer, J. & Bönisch, H. Oxybutynin and trospium are substrates of the human organic cation transporters. Naunyn-Schmied Arch Pharmacol 383, 203–208 (2011). https://doi.org/10.1007/s00210-010-0590-x

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  • DOI: https://doi.org/10.1007/s00210-010-0590-x

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