''Development of a physiologically based pharmacokinetic model for the crocetin in mice.''

Postgraduate Thesis uoadl:1692337 736 Read counter

Unit:
Κατεύθυνση Φαρμακευτική Τεχνολογία
Library of the School of Science
Deposit date:
2017-07-05
Year:
2017
Author:
Tsoutsi Dafni
Supervisors info:
1. Α. Δοκουμετζίδης
Επίκουρος καθηγητής Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών, Τμήματος Φαρμακευτικής, Τομέα Φαρμακευτικής Τεχνολογίας (επιβλέπων καθηγητής)
2. Γ. Βαλσαμή
Αναπληρώτρια καθηγήτρια Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών, Τμήματος Φαρμακευτικής, Τομέα Φαρμακευτικής Τεχνολογίας
3. Ε. Καραλής
Επίκουρος καθηγητής Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών, Τμήματος Φαρμακευτικής, Τομέα Φαρμακευτικής Τεχνολογίας
Original Title:
'' Ανάπτυξη Φυσιολογικού Φαρμακοκινητικού Μοντέλου για την ουσία της κροκετίνης σε ποντίκια. ''
Languages:
Greek
Translated title:
''Development of a physiologically based pharmacokinetic model for the crocetin in mice.''
Summary:
In the first chapter of the paper, a review is made of crocus Sativus L., its healing properties and its chemical composition. An increasing number of studies highlight the beneficial effects of crocus and its components on various systems and a variety of conditions. The production of saffron has been a major concern for the drug industry.
Of particular interest, from a chemical point of view, are the spots of the flower. The chemical analysis of plant extracts has shown that the main active ingredients of saffron are carotenoids, crocetin and crocin, which are due to its intense color and monterpenic aldehydes, picrocrocin and saffranal, where the first is responsible for the characteristic flavor of and the second gives the spice its special smell.
The crocins are unusually water soluble carotenoids due to their high glycosidic content. Hydrolysis products of crocin are gentiobiose and crocetin. Crocetin is a dicarboxylic acid which is hydrophobic. However, when esterified a water-soluble product results. The crocins are trans-glycosides of crocetin. Glycosylation occurs with the aid of enzymes which substantially convert the crocetin into a water-soluble and stable form, thereby improving its bioavailability. Until today, there are no data on the distribution of crocetin in the tissues. However, studies show the binding of crocetin to plasma albumin, indicating a possible mechanism of transfer of crocetin to the tissues.
In the second chapter, reference is made to the physiologically based pharmacokinetic models, the categories that are divided, in the development of such a model and the purpose used. Pharmacokinetics quantifies the processes of absorption, distribution, metabolism and excretion of pharmaceutical molecules into the body. The aim is to calculate the pharmacokinetic parameters, from the experimental data of analysis, to be used for the development of new molecules and for the improvement of the treatment. Scaling between species is another application of PBPK models. The aim is to predict the distribution of the molecule to a species for which there is no concentration-time data from tissues, based on a empirical model developed for another species from which such data has been obtained. By extending a PBPK model from one species to another, it is possible to predict the pharmacokinetics of the molecule in the second species and thus it is easier to determine the initial dose at the first administration of the drug to humans and reduce the likelihood of administering a subtherapeutic or toxic dose.
The third chapter presents the methods used to prepare this study. The purpose of this paper is to implement a PBPK model of crocetin in the Phoenix and Berkeley Madonna computational package, with data from mice. Initially, a first estimate of the structure of the model is made, then the equations of the model are described, describing the temporal change in the concentration of the molecule in the body, and finally, the required parameters are assessed for both the plasma and each tissue individually. The aim is to predict the temporal change in the concentration of the drug in blood and tissues. In the present study, 80 male 8-week-old mice received aqueous crocus extract. The dose was determined at 60 mg / kg of body weight of the lyophilized extract. The mice in each group were randomly assigned to groups of five. Animals were anesthetized and blood samples were collected at 5, 15, 30, 60, 90, 120, 180 and 240 minutes after cardioversion. Tissue sampling (heart, liver, lungs and kidneys) was also conducted at the same time points.
The fourth and final chapter presents the results and conclusions. During the data analysis process, the PBPK model was initially adapted to plasma data and the serum concentration-time profile was simulated through the Phoenix program. Thereafter, plasma parameters were evaluated for intravenous administration (IV) and for oral administration (per os), both for crocetin and for its metabolite, namely, crocetin glucuronide. This profile is used as an input function for the estimation of Kp, CL and PS parameters with open loop models for each of the tissues, both with the perfusion limited tissue model, where the tissue is considered a single model, and with the permeability limited tissue model.
The model that best described the data was the one-compartment model with first-class removal kinetics. The models were evaluated for their adaptation to experimental data, their stability and their foresight abilities. Finally, the most suitable and most reliable model is selected.
Main subject category:
Science
Other subject categories:
Pharmaceutical technology
Keywords:
crocus, crocin, crocetin, pharmacokinetic
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
65
Number of pages:
87
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