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Development and performance verification of the pharmacokinetic model towards determination of the active drug fraction surrogate in the heart tissue

Tytuł: Development and performance verification of the pharmacokinetic model towards determination of the active drug fraction surrogate in the heart tissue

Autor:

Tylutki, Zofia

Data:

2018

Typ:

Praca doktorska

Abstrakt:

Accurate prediction of drug effect is invaluable in terms of both safety and efficacy. Cardioactive drugs may trigger their effects by binding to the targets from either the extra- or intracellular side of the sarcolemma. Knowledge of a drug concentration at its site of action is strongly needed to comprehend the exposure-response relationship and avoid the bias of the hysteresis effect in response vs. time profiles. The herein described doctoral project aimed to provide the tool, namely a physiologically-based cardiac pharmacokinetic model, which would be useful in assessment of the cardiac active drug fraction surrogate responsible for the clinically observed drug-related electrophysiological response in humans. Besides the model development, the concurrent goal of this research was to verify the model performance. The doctoral project resulted in establishment of the multicompartmental heart model structure nested in the full-PBPK model linked to the minimal-PBPK model for the metabolite. The final structure accounts for cardiac metabolism, passive diffusion and active transport as the ways of drug distribution within heart tissue, and distinguishes between extra- and intracellular spaces. It allows for the estimation of cardiac concentration of both parent compound and metabolites with inter-individual variability. Amitriptyline and its main metabolite, nortriptyline, were chosen as the exemplary drugs for model performance. The model was verified in terms of pharmacokinetics and the usefulness of predicted cardiac concentrations for modeling of amitriptyline-related electrophysiological effect.

Miejsce wydania:

Kraków

Stopień studiów:

2 - studia doktoranckie

Dyscyplina:

farmakologia

Instytucja nadająca tytuł:

Jagiellonian University. Medical College. Faculty of Pharmacy. Department of Social Pharmacy. Unit of Parmacoepidemiology and Pharmacoeconomics.

Promotor:

Sebastian Polak

Data wydania:

2018

Identyfikator:

oai:dl.cm-uj.krakow.pl:4298

Sygnatura:

ZB-129271

ControlNumberVIRTUA:

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Prawa dostępu:

nieograniczony

Lokalizacja oryginału:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Temat i słowa kluczowe:

pharmacokinetics PBPK modeling drug safety

Kolekcje, do których przypisany jest obiekt:

Data ostatniej modyfikacji:

24 maj 2021

Data dodania obiektu:

9 lip 2019

Liczba wyświetleń treści obiektu:

101

Wszystkie dostępne wersje tego obiektu:

http://dl.cm-uj.krakow.pl:8080/publication/4299

Wyświetl opis w formacie RDF:

RDF

Wyświetl opis w formacie OAI-PMH:

OAI-PMH

Nazwa wydania Data
ZB-129271 24 maj 2021

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Adres

Biblioteka Medyczna
ul. Medyczna 7
30-688 Kraków

Telefon

12 658 72 56
517 385 669

E-Mail

Oddział Gromadzenia i Opracowania Zbiorów
cyfrowabm@cm-uj.krakow.pl

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