Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes

Autores
Riva, Natalia; Molina, Manuel; Larsen, Karen Elizabeth; Trezeguet Renatti, Guido; Caceres Guido, Paulo Arturo; Bressan, Ignacio Guillermo; Licciardone, Nieves; Monteverde, Marta; Schaiquevich, Paula Susana; Virkel, Guillermo Leon
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.
Fil: Riva, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Larsen, Karen Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Trezeguet Renatti, Guido. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Caceres Guido, Paulo Arturo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Bressan, Ignacio Guillermo. Hospital Italiano; Argentina
Fil: Licciardone, Nieves. Hospital Italiano; Argentina
Fil: Monteverde, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
LXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de Nanomedicinas
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
Materia
TACROLIMUS
MEROPENEM
CYP 3A
LIVER
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:11336/165379
Acceder
id CONICETDig_7a23adbebf4d5c1f090aece2b8a5031e
oai_identifier_str oai:ri.conicet.gov.ar:11336/165379
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomesRiva, NataliaMolina, ManuelLarsen, Karen ElizabethTrezeguet Renatti, GuidoCaceres Guido, Paulo ArturoBressan, Ignacio GuillermoLicciardone, NievesMonteverde, MartaSchaiquevich, Paula SusanaVirkel, Guillermo LeonTACROLIMUSMEROPENEMCYP 3ALIVERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.Fil: Riva, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Larsen, Karen Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Trezeguet Renatti, Guido. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caceres Guido, Paulo Arturo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Bressan, Ignacio Guillermo. Hospital Italiano; ArgentinaFil: Licciardone, Nieves. Hospital Italiano; ArgentinaFil: Monteverde, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaLXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de NanomedicinasArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de NanomedicinasFundación Revista Medicina2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/165379Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes; LXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de Nanomedicinas ; Argentina; 2021; 95-950025-7680CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:03:34Zoai:ri.conicet.gov.ar:11336/165379instacron: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:34982025-09-03 10:03:35.265CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
title Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
spellingShingle Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
Riva, Natalia
TACROLIMUS
MEROPENEM
CYP 3A
LIVER
title_short Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
title_full Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
title_fullStr Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
title_full_unstemmed Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
title_sort Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes
dc.creator.none.fl_str_mv Riva, Natalia
Molina, Manuel
Larsen, Karen Elizabeth
Trezeguet Renatti, Guido
Caceres Guido, Paulo Arturo
Bressan, Ignacio Guillermo
Licciardone, Nieves
Monteverde, Marta
Schaiquevich, Paula Susana
Virkel, Guillermo Leon
author Riva, Natalia
author_facet Riva, Natalia
Molina, Manuel
Larsen, Karen Elizabeth
Trezeguet Renatti, Guido
Caceres Guido, Paulo Arturo
Bressan, Ignacio Guillermo
Licciardone, Nieves
Monteverde, Marta
Schaiquevich, Paula Susana
Virkel, Guillermo Leon
author_role author
author2 Molina, Manuel
Larsen, Karen Elizabeth
Trezeguet Renatti, Guido
Caceres Guido, Paulo Arturo
Bressan, Ignacio Guillermo
Licciardone, Nieves
Monteverde, Marta
Schaiquevich, Paula Susana
Virkel, Guillermo Leon
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TACROLIMUS
MEROPENEM
CYP 3A
LIVER
topic TACROLIMUS
MEROPENEM
CYP 3A
LIVER
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.
Fil: Riva, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Larsen, Karen Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Trezeguet Renatti, Guido. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Caceres Guido, Paulo Arturo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Bressan, Ignacio Guillermo. Hospital Italiano; Argentina
Fil: Licciardone, Nieves. Hospital Italiano; Argentina
Fil: Monteverde, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
LXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de Nanomedicinas
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Asociación Argentina de Farmacología Experimental
Asociación Argentina de Nanomedicinas
description Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/165379
Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes; LXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de Nanomedicinas ; Argentina; 2021; 95-95
0025-7680
CONICET Digital
CONICET
url http://hdl.handle.net/11336/165379
identifier_str_mv Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes; LXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de Nanomedicinas ; Argentina; 2021; 95-95
0025-7680
CONICET Digital
CONICET
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language eng
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dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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reponame_str CONICET Digital (CONICET)
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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
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