Oxybutynin and trospium are substrates of the human organic cation transporters

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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Wenge, Birger [verfasserIn] Geyer, Joachim Bönisch, Heinz

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2011

Schlagwörter:	Oxybutynin Trospium Organic cation transporter

Anmerkung:	© Springer-Verlag 2011

Übergeordnetes Werk:	Enthalten in: Naunyn-Schmiedeberg's archives of pharmacology - Berlin : Springer, 1873, 383(2011), 2 vom: 07. Jan., Seite 203-208
Übergeordnetes Werk:	volume:383 ; year:2011 ; number:2 ; day:07 ; month:01 ; pages:203-208

Links:	Volltext

DOI / URN:	10.1007/s00210-010-0590-x

Katalog-ID:	SPR001955942

Internformat


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100	1		\|a Wenge, Birger \|e verfasserin \|4 aut
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520			\|a 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder.
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700	1		\|a Bönisch, Heinz \|4 aut
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912			\|a GBV_ILN_32
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
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912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_90
912			\|a GBV_ILN_95
912			\|a GBV_ILN_100
912			\|a GBV_ILN_101
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_120
912			\|a GBV_ILN_138
912			\|a GBV_ILN_150
912			\|a GBV_ILN_151
912			\|a GBV_ILN_152
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_171
912			\|a GBV_ILN_187
912			\|a GBV_ILN_213
912			\|a GBV_ILN_224
912			\|a GBV_ILN_230
912			\|a GBV_ILN_250
912			\|a GBV_ILN_267
912			\|a GBV_ILN_281
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_370
912			\|a GBV_ILN_602
912			\|a GBV_ILN_636
912			\|a GBV_ILN_702
912			\|a GBV_ILN_2001
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2004
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2006
912			\|a GBV_ILN_2007
912			\|a GBV_ILN_2008
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2010
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2015
912			\|a GBV_ILN_2020
912			\|a GBV_ILN_2021
912			\|a GBV_ILN_2025
912			\|a GBV_ILN_2026
912			\|a GBV_ILN_2027
912			\|a GBV_ILN_2031
912			\|a GBV_ILN_2034
912			\|a GBV_ILN_2037
912			\|a GBV_ILN_2038
912			\|a GBV_ILN_2039
912			\|a GBV_ILN_2044
912			\|a GBV_ILN_2048
912			\|a GBV_ILN_2049
912			\|a GBV_ILN_2050
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2057
912			\|a GBV_ILN_2059
912			\|a GBV_ILN_2061
912			\|a GBV_ILN_2064
912			\|a GBV_ILN_2065
912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2070
912			\|a GBV_ILN_2086
912			\|a GBV_ILN_2088
912			\|a GBV_ILN_2093
912			\|a GBV_ILN_2106
912			\|a GBV_ILN_2107
912			\|a GBV_ILN_2108
912			\|a GBV_ILN_2110
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_2112
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912			\|a GBV_ILN_2152
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912			\|a GBV_ILN_2336
912			\|a GBV_ILN_2446
912			\|a GBV_ILN_2470
912			\|a GBV_ILN_2472
912			\|a GBV_ILN_2507
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912			\|a GBV_ILN_2548
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4046
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4242
912			\|a GBV_ILN_4246
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4326
912			\|a GBV_ILN_4328
912			\|a GBV_ILN_4333
912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4336
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4393
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 383 \|j 2011 \|e 2 \|b 07 \|c 01 \|h 203-208

Indexfelder

author_variant	b w bw j g jg h b hb
matchkey_str	article:14321912:2011----::xbtnnntopuaeusrtsfhhmnrai
hierarchy_sort_str	2011
publishDate	2011
allfields	10.1007/s00210-010-0590-x doi (DE-627)SPR001955942 (SPR)s00210-010-0590-x-e DE-627 ger DE-627 rakwb eng Wenge, Birger verfasserin aut Oxybutynin and trospium are substrates of the human organic cation transporters 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag 2011 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213 Geyer, Joachim aut Bönisch, Heinz aut Enthalten in Naunyn-Schmiedeberg's archives of pharmacology Berlin : Springer, 1873 383(2011), 2 vom: 07. Jan., Seite 203-208 (DE-627)254638309 (DE-600)1462940-9 1432-1912 nnns volume:383 year:2011 number:2 day:07 month:01 pages:203-208 https://dx.doi.org/10.1007/s00210-010-0590-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 383 2011 2 07 01 203-208
spelling	10.1007/s00210-010-0590-x doi (DE-627)SPR001955942 (SPR)s00210-010-0590-x-e DE-627 ger DE-627 rakwb eng Wenge, Birger verfasserin aut Oxybutynin and trospium are substrates of the human organic cation transporters 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag 2011 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213 Geyer, Joachim aut Bönisch, Heinz aut Enthalten in Naunyn-Schmiedeberg's archives of pharmacology Berlin : Springer, 1873 383(2011), 2 vom: 07. Jan., Seite 203-208 (DE-627)254638309 (DE-600)1462940-9 1432-1912 nnns volume:383 year:2011 number:2 day:07 month:01 pages:203-208 https://dx.doi.org/10.1007/s00210-010-0590-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 383 2011 2 07 01 203-208
allfields_unstemmed	10.1007/s00210-010-0590-x doi (DE-627)SPR001955942 (SPR)s00210-010-0590-x-e DE-627 ger DE-627 rakwb eng Wenge, Birger verfasserin aut Oxybutynin and trospium are substrates of the human organic cation transporters 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag 2011 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213 Geyer, Joachim aut Bönisch, Heinz aut Enthalten in Naunyn-Schmiedeberg's archives of pharmacology Berlin : Springer, 1873 383(2011), 2 vom: 07. Jan., Seite 203-208 (DE-627)254638309 (DE-600)1462940-9 1432-1912 nnns volume:383 year:2011 number:2 day:07 month:01 pages:203-208 https://dx.doi.org/10.1007/s00210-010-0590-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 383 2011 2 07 01 203-208
allfieldsGer	10.1007/s00210-010-0590-x doi (DE-627)SPR001955942 (SPR)s00210-010-0590-x-e DE-627 ger DE-627 rakwb eng Wenge, Birger verfasserin aut Oxybutynin and trospium are substrates of the human organic cation transporters 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag 2011 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213 Geyer, Joachim aut Bönisch, Heinz aut Enthalten in Naunyn-Schmiedeberg's archives of pharmacology Berlin : Springer, 1873 383(2011), 2 vom: 07. Jan., Seite 203-208 (DE-627)254638309 (DE-600)1462940-9 1432-1912 nnns volume:383 year:2011 number:2 day:07 month:01 pages:203-208 https://dx.doi.org/10.1007/s00210-010-0590-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 383 2011 2 07 01 203-208
allfieldsSound	10.1007/s00210-010-0590-x doi (DE-627)SPR001955942 (SPR)s00210-010-0590-x-e DE-627 ger DE-627 rakwb eng Wenge, Birger verfasserin aut Oxybutynin and trospium are substrates of the human organic cation transporters 2011 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag 2011 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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213 Geyer, Joachim aut Bönisch, Heinz aut Enthalten in Naunyn-Schmiedeberg's archives of pharmacology Berlin : Springer, 1873 383(2011), 2 vom: 07. Jan., Seite 203-208 (DE-627)254638309 (DE-600)1462940-9 1432-1912 nnns volume:383 year:2011 number:2 day:07 month:01 pages:203-208 https://dx.doi.org/10.1007/s00210-010-0590-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 383 2011 2 07 01 203-208
language	English
source	Enthalten in Naunyn-Schmiedeberg's archives of pharmacology 383(2011), 2 vom: 07. Jan., Seite 203-208 volume:383 year:2011 number:2 day:07 month:01 pages:203-208
sourceStr	Enthalten in Naunyn-Schmiedeberg's archives of pharmacology 383(2011), 2 vom: 07. Jan., Seite 203-208 volume:383 year:2011 number:2 day:07 month:01 pages:203-208
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Oxybutynin Trospium Organic cation transporter
isfreeaccess_bool	false
container_title	Naunyn-Schmiedeberg's archives of pharmacology
authorswithroles_txt_mv	Wenge, Birger @@aut@@ Geyer, Joachim @@aut@@ Bönisch, Heinz @@aut@@
publishDateDaySort_date	2011-01-07T00:00:00Z
hierarchy_top_id	254638309
id	SPR001955942
language_de	englisch
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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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Oxybutynin</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Trospium</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Organic cation transporter</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Geyer, Joachim</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bönisch, Heinz</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Naunyn-Schmiedeberg's archives of pharmacology</subfield><subfield code="d">Berlin : Springer, 1873</subfield><subfield code="g">383(2011), 2 vom: 07. 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author	Wenge, Birger
spellingShingle	Wenge, Birger misc Oxybutynin misc Trospium misc Organic cation transporter Oxybutynin and trospium are substrates of the human organic cation transporters
authorStr	Wenge, Birger
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topic_title	Oxybutynin and trospium are substrates of the human organic cation transporters Oxybutynin (dpeaa)DE-He213 Trospium (dpeaa)DE-He213 Organic cation transporter (dpeaa)DE-He213
topic	misc Oxybutynin misc Trospium misc Organic cation transporter
topic_unstemmed	misc Oxybutynin misc Trospium misc Organic cation transporter
topic_browse	misc Oxybutynin misc Trospium misc Organic cation transporter
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
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title	Oxybutynin and trospium are substrates of the human organic cation transporters
ctrlnum	(DE-627)SPR001955942 (SPR)s00210-010-0590-x-e
title_full	Oxybutynin and trospium are substrates of the human organic cation transporters
author_sort	Wenge, Birger
journal	Naunyn-Schmiedeberg's archives of pharmacology
journalStr	Naunyn-Schmiedeberg's archives of pharmacology
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container_start_page	203
author_browse	Wenge, Birger Geyer, Joachim Bönisch, Heinz
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format_se	Elektronische Aufsätze
author-letter	Wenge, Birger
doi_str_mv	10.1007/s00210-010-0590-x
title_sort	oxybutynin and trospium are substrates of the human organic cation transporters
title_auth	Oxybutynin and trospium are substrates of the human organic cation transporters
abstract	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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. © Springer-Verlag 2011
abstractGer	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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. © Springer-Verlag 2011
abstract_unstemmed	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 ($ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $). 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 $ hOCT_{1} $, $ hOCT_{2} $ or $ hOCT_{3} $. In addition, we determined $ IC_{50} $ 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 $ IC_{50} $ values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at $ hOCT_{1} $ with Km of 8 μM and Vmax of 484 pmol/mg protein/min. The rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific oxybutynin uptake was $ hOCT_{1} $ > $ hOCT_{2} $ = $ hOCT_{3} $. 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 $ IC_{50} $ values of 18, 1.4 and 710 μM (at $ hOCT_{1} $, $ hOCT_{2} $ and $ hOCT_{3} $, respectively) and Km values of 17 and 8 μM and about identical Vmax values of about 90 pmol/mg protein/min at $ hOCT_{1} $ and $ hOCT_{2} $, respectively; the rank order of affinity (1/$ IC_{50} $ or 1/Km) of specific uptake of trospium was $ hOCT_{2} $ > $ hOCT_{1} $ > > $ hOCT_{3} $. Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, $ hOCT_{1} $ and $ hOCT_{3} $ may be involved in the tissue uptake of this drug in the urinary bladder. © Springer-Verlag 2011
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container_issue	2
title_short	Oxybutynin and trospium are substrates of the human organic cation transporters
url	https://dx.doi.org/10.1007/s00210-010-0590-x
remote_bool	true
author2	Geyer, Joachim Bönisch, Heinz
author2Str	Geyer, Joachim Bönisch, Heinz
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doi_str	10.1007/s00210-010-0590-x
up_date	2024-07-04T01:08:22.677Z
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Oxybutynin and trospium are substrates of the human organic cation transporters

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