Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine

Autores
Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A.; Mahfouz, Reda; Peng Ng, Kwok; Negrotto, Soledad; Smith, Nicola; Terse, Pramod; Engelke, Kory J.; Covey, Joseph; Chan, Kenneth K.; DeSimone, Joseph; Saunthararajah, Yogen
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2x/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.
Fil: Lavelle, Donald. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Vaitkus, Kestis. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Ling, Yonghua. Ohio State University; Estados Unidos
Fil: Ruiz, Maria A.. University of Illinois at Chicago; Estados Unidos
Fil: Mahfouz, Reda. Cleveland Clinic; Estados Unidos
Fil: Peng Ng, Kwok. Cleveland Clinic; Estados Unidos
Fil: Negrotto, Soledad. Cleveland Clinic; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Smith, Nicola. National Cancer Institute; Estados Unidos
Fil: Terse, Pramod. National Cancer Institute; Estados Unidos
Fil: Engelke, Kory J.. Avanza Laboratories; Estados Unidos
Fil: Covey, Joseph. National Cancer Institute; Estados Unidos
Fil: Chan, Kenneth K.. Ohio State University; Estados Unidos
Fil: DeSimone, Joseph. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Saunthararajah, Yogen. University of Illinois at Chicago; Estados Unidos. Cleveland Clinic; Estados Unidos
Materia
Decitabine
Tetrahydrouridine
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:11336/91413
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/91413
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabineLavelle, DonaldVaitkus, KestisLing, YonghuaRuiz, Maria A.Mahfouz, RedaPeng Ng, KwokNegrotto, SoledadSmith, NicolaTerse, PramodEngelke, Kory J.Covey, JosephChan, Kenneth K.DeSimone, JosephSaunthararajah, YogenDecitabineTetrahydrouridinehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2x/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.Fil: Lavelle, Donald. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados UnidosFil: Vaitkus, Kestis. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados UnidosFil: Ling, Yonghua. Ohio State University; Estados UnidosFil: Ruiz, Maria A.. University of Illinois at Chicago; Estados UnidosFil: Mahfouz, Reda. Cleveland Clinic; Estados UnidosFil: Peng Ng, Kwok. Cleveland Clinic; Estados UnidosFil: Negrotto, Soledad. Cleveland Clinic; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Smith, Nicola. National Cancer Institute; Estados UnidosFil: Terse, Pramod. National Cancer Institute; Estados UnidosFil: Engelke, Kory J.. Avanza Laboratories; Estados UnidosFil: Covey, Joseph. National Cancer Institute; Estados UnidosFil: Chan, Kenneth K.. Ohio State University; Estados UnidosFil: DeSimone, Joseph. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados UnidosFil: Saunthararajah, Yogen. University of Illinois at Chicago; Estados Unidos. Cleveland Clinic; Estados UnidosAmerican Society of Hematology2012-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/91413Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A.; Mahfouz, Reda; et al.; Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine; American Society of Hematology; Blood; 119; 5; 2-2012; 1240-12470006-4971CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2011-08-371690info:eu-repo/semantics/altIdentifier/url/https://ashpublications.org/blood/article/119/5/1240/29815/Effects-of-tetrahydrouridine-on-pharmacokineticsinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:50Zoai:ri.conicet.gov.ar:11336/91413instacron: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 09:59:51.132CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
title Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
spellingShingle Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
Lavelle, Donald
Decitabine
Tetrahydrouridine
title_short Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
title_full Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
title_fullStr Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
title_full_unstemmed Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
title_sort Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
dc.creator.none.fl_str_mv Lavelle, Donald
Vaitkus, Kestis
Ling, Yonghua
Ruiz, Maria A.
Mahfouz, Reda
Peng Ng, Kwok
Negrotto, Soledad
Smith, Nicola
Terse, Pramod
Engelke, Kory J.
Covey, Joseph
Chan, Kenneth K.
DeSimone, Joseph
Saunthararajah, Yogen
author Lavelle, Donald
author_facet Lavelle, Donald
Vaitkus, Kestis
Ling, Yonghua
Ruiz, Maria A.
Mahfouz, Reda
Peng Ng, Kwok
Negrotto, Soledad
Smith, Nicola
Terse, Pramod
Engelke, Kory J.
Covey, Joseph
Chan, Kenneth K.
DeSimone, Joseph
Saunthararajah, Yogen
author_role author
author2 Vaitkus, Kestis
Ling, Yonghua
Ruiz, Maria A.
Mahfouz, Reda
Peng Ng, Kwok
Negrotto, Soledad
Smith, Nicola
Terse, Pramod
Engelke, Kory J.
Covey, Joseph
Chan, Kenneth K.
DeSimone, Joseph
Saunthararajah, Yogen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Decitabine
Tetrahydrouridine
topic Decitabine
Tetrahydrouridine
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 deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2x/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.
Fil: Lavelle, Donald. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Vaitkus, Kestis. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Ling, Yonghua. Ohio State University; Estados Unidos
Fil: Ruiz, Maria A.. University of Illinois at Chicago; Estados Unidos
Fil: Mahfouz, Reda. Cleveland Clinic; Estados Unidos
Fil: Peng Ng, Kwok. Cleveland Clinic; Estados Unidos
Fil: Negrotto, Soledad. Cleveland Clinic; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Smith, Nicola. National Cancer Institute; Estados Unidos
Fil: Terse, Pramod. National Cancer Institute; Estados Unidos
Fil: Engelke, Kory J.. Avanza Laboratories; Estados Unidos
Fil: Covey, Joseph. National Cancer Institute; Estados Unidos
Fil: Chan, Kenneth K.. Ohio State University; Estados Unidos
Fil: DeSimone, Joseph. University of Illinois at Chicago; Estados Unidos. Jesse Brown VA Medical Center; Estados Unidos
Fil: Saunthararajah, Yogen. University of Illinois at Chicago; Estados Unidos. Cleveland Clinic; Estados Unidos
description The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2x/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.
publishDate 2012
dc.date.none.fl_str_mv 2012-02
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/11336/91413
Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A.; Mahfouz, Reda; et al.; Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine; American Society of Hematology; Blood; 119; 5; 2-2012; 1240-1247
0006-4971
CONICET Digital
CONICET
url http://hdl.handle.net/11336/91413
identifier_str_mv Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A.; Mahfouz, Reda; et al.; Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine; American Society of Hematology; Blood; 119; 5; 2-2012; 1240-1247
0006-4971
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2011-08-371690
info:eu-repo/semantics/altIdentifier/url/https://ashpublications.org/blood/article/119/5/1240/29815/Effects-of-tetrahydrouridine-on-pharmacokinetics
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 American Society of Hematology
publisher.none.fl_str_mv American Society of Hematology
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_ 1842269605055168512
score 13.13397

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