Pharmacokinetic/Pharmacodynamic Models of an Alzheimer’s Drug, Donepezil, in Rats

Kiriyama, Akiko; Kimura, Satoshi; Yamashita, Shugo

doi:10.1124/dmd.122.001061

Cited by 3 publications

(2 citation statements)

References 37 publications

(39 reference statements)

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“…Compartmental analysis facilitates the assessment of blood retention and tumor migration of small-molecule drugs using rate constants. , This indicates that drug release characteristics can be indirectly assessed by detecting and predicting the PK of nanoparticles administered to biological systems by using compartmental analysis. Similar to PK analysis, this evaluation of the chemical reaction kinetics of nanoparticles has sparked a debate on the effectiveness of drug release systems such as lysosomal-mediated drug release via sulfide bond in tumor pathology and DDS. , Chemical reaction rate analysis necessitates in vitro experiments and frequent sampling using the stopped-flow method .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Yamashita,

Imanishi,

Ueki

et al. 2024

Mol. Pharmaceutics

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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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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Yamashita,

Imanishi,

Ueki

et al. 2024

Mol. Pharmaceutics

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“…Consequently, scientific descriptions of drug dosage, pharmacokinetics (PKs), and effects and/or adverse effects can be quantitatively assessed using a PK‐pharmacodynamic (PD) (PK‐PD) modeling techniques. 1 , 2 , 3 , 4 Previously, we assessed the PK and PD of nifedipine and propranolol using rats as experimental animals. 5 Blood pressure (BP) reduction was assessed as a main effect, whereas heart rate (HR) and QT interval (QT) were assessed as adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic‐pharmacodynamic analyses

Kiriyama,

Kimura,

Yamashita

2024

Pharmacology Res & Perspec

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This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half‐life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

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Evaluation of anticancer effect of micelle-encapsulated doxorubicin using gamma-distributed delay model

Yamashita,

Kume,

Tsujimoto

et al. 2024

Journal of Drug Delivery Science and Technology

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Pharmacokinetic/Pharmacodynamic Models of an Alzheimer’s Drug, Donepezil, in Rats

Cited by 3 publications

References 37 publications

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic‐pharmacodynamic analyses

Evaluation of anticancer effect of micelle-encapsulated doxorubicin using gamma-distributed delay model

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