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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/189193
Acceder
id CONICETDig_8f9e03cdc2c12dd7f5c9f26a35b95085
oai_identifier_str oai:ri.conicet.gov.ar:11336/189193
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv 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
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.eurekaselect.com/article/39042
info:eu-repo/semantics/altIdentifier/doi/10.2174/187231210792928251
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Bentham Science Publishers
publisher.none.fl_str_mv Bentham Science Publishers
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781713117609984
score 12.928904

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