P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice
- Autores
- Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; Schaiquevich, Paula Susana; Fraga, Charles H.; Panetta, John C.; Waters, Christopher M.; Stewart, Clinton F.
- Año de publicación
- 2010
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.
Fil: Tagen, Michael. St. Jude Children's Research Hospital; Estados Unidos
Fil: Zhuang, Yanli. St. Jude Children's Research Hospital; Estados Unidos
Fil: Zhang, Fan. St. Jude Children's Research Hospital; Estados Unidos
Fil: Harstead, K. Elaine. St. Jude Children's Research Hospital; Estados Unidos
Fil: Shen, Jun. St. Jude Children's Research Hospital; Estados Unidos
Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. St. Jude Children's Research Hospital; Estados Unidos
Fil: Fraga, Charles H.. St. Jude Children's Research Hospital; Estados Unidos
Fil: Panetta, John C.. St. Jude Children's Research Hospital; Estados Unidos
Fil: Waters, Christopher M.. St. Jude Children's Research Hospital; Estados Unidos
Fil: Stewart, Clinton F.. St. Jude Children's Research Hospital; Estados Unidos - Materia
-
IRINOTECAN
P-GLYCOPROTEIN
MDR4 - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/189193
Ver los metadatos del registro completo
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P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in miceTagen, MichaelZhuang, YanliZhang, FanHarstead, K. ElaineShen, JunSchaiquevich, Paula SusanaFraga, Charles H.Panetta, John C.Waters, Christopher M.Stewart, Clinton F.IRINOTECANP-GLYCOPROTEINMDR4https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.Fil: Tagen, Michael. St. Jude Children's Research Hospital; Estados UnidosFil: Zhuang, Yanli. St. Jude Children's Research Hospital; Estados UnidosFil: Zhang, Fan. St. Jude Children's Research Hospital; Estados UnidosFil: Harstead, K. Elaine. St. Jude Children's Research Hospital; Estados UnidosFil: Shen, Jun. St. Jude Children's Research Hospital; Estados UnidosFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. St. Jude Children's Research Hospital; Estados UnidosFil: Fraga, Charles H.. St. Jude Children's Research Hospital; Estados UnidosFil: Panetta, John C.. St. Jude Children's Research Hospital; Estados UnidosFil: Waters, Christopher M.. St. Jude Children's Research Hospital; Estados UnidosFil: Stewart, Clinton F.. St. Jude Children's Research Hospital; Estados UnidosBentham Science Publishers2010-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/189193Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; et al.; P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice; Bentham Science Publishers; Drug Metabolism Letters; 4; 4; 6-2010; 195-2011872-3128CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.eurekaselect.com/article/39042info:eu-repo/semantics/altIdentifier/doi/10.2174/187231210792928251info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:21:14Zoai:ri.conicet.gov.ar:11336/189193instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:21:14.978CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| title |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| spellingShingle |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice Tagen, Michael IRINOTECAN P-GLYCOPROTEIN MDR4 |
| title_short |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| title_full |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| title_fullStr |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| title_full_unstemmed |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| title_sort |
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice |
| dc.creator.none.fl_str_mv |
Tagen, Michael Zhuang, Yanli Zhang, Fan Harstead, K. Elaine Shen, Jun Schaiquevich, Paula Susana Fraga, Charles H. Panetta, John C. Waters, Christopher M. Stewart, Clinton F. |
| author |
Tagen, Michael |
| author_facet |
Tagen, Michael Zhuang, Yanli Zhang, Fan Harstead, K. Elaine Shen, Jun Schaiquevich, Paula Susana Fraga, Charles H. Panetta, John C. Waters, Christopher M. Stewart, Clinton F. |
| author_role |
author |
| author2 |
Zhuang, Yanli Zhang, Fan Harstead, K. Elaine Shen, Jun Schaiquevich, Paula Susana Fraga, Charles H. Panetta, John C. Waters, Christopher M. Stewart, Clinton F. |
| author2_role |
author author author author author author author author author |
| dc.subject.none.fl_str_mv |
IRINOTECAN P-GLYCOPROTEIN MDR4 |
| topic |
IRINOTECAN P-GLYCOPROTEIN MDR4 |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics. Fil: Tagen, Michael. St. Jude Children's Research Hospital; Estados Unidos Fil: Zhuang, Yanli. St. Jude Children's Research Hospital; Estados Unidos Fil: Zhang, Fan. St. Jude Children's Research Hospital; Estados Unidos Fil: Harstead, K. Elaine. St. Jude Children's Research Hospital; Estados Unidos Fil: Shen, Jun. St. Jude Children's Research Hospital; Estados Unidos Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. St. Jude Children's Research Hospital; Estados Unidos Fil: Fraga, Charles H.. St. Jude Children's Research Hospital; Estados Unidos Fil: Panetta, John C.. St. Jude Children's Research Hospital; Estados Unidos Fil: Waters, Christopher M.. St. Jude Children's Research Hospital; Estados Unidos Fil: Stewart, Clinton F.. St. Jude Children's Research Hospital; Estados Unidos |
| description |
The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics. |
| publishDate |
2010 |
| dc.date.none.fl_str_mv |
2010-06 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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article |
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publishedVersion |
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http://hdl.handle.net/11336/189193 Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; et al.; P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice; Bentham Science Publishers; Drug Metabolism Letters; 4; 4; 6-2010; 195-201 1872-3128 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/189193 |
| identifier_str_mv |
Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; et al.; P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice; Bentham Science Publishers; Drug Metabolism Letters; 4; 4; 6-2010; 195-201 1872-3128 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
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eng |
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info:eu-repo/semantics/altIdentifier/url/https://www.eurekaselect.com/article/39042 info:eu-repo/semantics/altIdentifier/doi/10.2174/187231210792928251 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf |
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Bentham Science Publishers |
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Bentham Science Publishers |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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