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Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.
Yamashita, Shugo; Imanishi, Azusa; Ueki, Suzuna; Okamoto, Serina; Kimura, Shunsuke; Kiriyama, Akiko.
Afiliación
  • Yamashita S; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
  • Imanishi A; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
  • Ueki S; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
  • Okamoto S; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
  • Kimura S; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
  • Kiriyama A; Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
Mol Pharm ; 21(7): 3173-3185, 2024 Jul 01.
Article en En | MEDLINE | ID: mdl-38798088
ABSTRACT
This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Ácido Fólico / Micelas Límite: Animals / Female / Humans Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Ácido Fólico / Micelas Límite: Animals / Female / Humans Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos