Farmakokinetička karakterizacija aloina i aloe emodina biomimetičkom kromatografijom i in silico metodama

master's thesis

• Title (english): Pharmacokinetic characterization of aloin and aloe emodin by biomimetic chromatography and in silico methods
• Author: Katarina Rudec
• Mentor: Ana Mornar Turk (mentor)
• Committee member: Ana Mornar Turk (predsjednik povjerenstva)
• Committee member: Domagoj Kifer (član povjerenstva)
• Committee member: Daniela Amidžić Klarić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of pharmaceutical analysis); Zagreb
• Defense date and country: 2023-04-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

U složenom i skupom procesu kakav je razvoj novog lijeka, svako unaprjeđenje, pojednostavljenje ili ubrzanje postupka mnogo vrijedi. Većina molekula kandidata odbacuje se već u ranim fazama razvoja zbog nepovoljnih farmakokinetičkih karakteristika koje su usko vezane uz fizikalno-kemijska svojstva spoja – lipofilnost, topljivost u vodi, afinitet vezanja za proteine, afinitet za biomembrane i sl. Stoga su metode kojima se takva svojstva određuju od posebnog značaja. Među njima su QSAR i QSPR računalne metode kojima se pomoću računalnih algoritama predviđaju različita svojstva molekule, kao i metode biomimetičke kromatografije kojima se in vitro ispituju takva svojstva. Ovaj rad obuhvaća farmakokinetičku karakterizaciju dviju biološki aktivnih tvari koje se koriste u terapiji upalnih bolesti crijeva – aloin i aloe emodin. Karakterizirani su prvo nizom QSPR metoda koje izračunavaju njihovu lipofilnost, topljivost, humanu crijevnu apsorpciju, oralnu bioraspoloživost te postotak vezanja za proteine plazme, a potom obrnuto-faznom tankoslojnom kromatografijom i obrnuto-faznom tekućinskom kromatografijom visoke djelotvornosti koje pokazuju hidrofobnost analita, tekućinskom kromatografijom visoke djelotvornosti sa stacionarnom fazom koja sadrži imobilizirane umjetne membrane koja pokazuje lipofilnost, zatim sa stacionarnom fazom koja sadrži imobilizirani humani serumski albumin i konačno onom koja sadrži imobilizirani α1-kiseli glikoprotein kojima se dobiva afinitet vezanja analita za HSA i AGP. U konačnici pokazano je kako je aloe emodin hidrofobniji od aloina, manje je topljiv u vodi, ima veću apsorpciju u crijevu kao i oralnu bioraspoloživost te se s većim afinitetom veže za proteine plazme u odnosu na aloin. Pritom su odstupanja među različitim QSPR izračunima vrlo velika i ostaje najpouzdanije farmakokinetička svojstva ispitivati in vitro metodama.

Abstract (english)

In a complex and expensive process such as the development of a new drug, any improvement, simplification or acceleration of the process is worth a lot. Most of the candidate molecules are rejected already in the early stages of development due to unfavorable pharmacokinetic characteristics that are closely related to the physicochemical properties of the compound – lipophilicity, water solubility, binding affinity for proteins, affinity for biomembranes, etc. Therefore, methods used to determine such properties are of special importance. Among them are QSAR and QSPR computer methods that use computer algorithms to predict various properties of a molecule, as well as biomimetic chromatography methods that test such properties in vitro. This paper includes the pharmacokinetic characterization of two biologically active substances used in therapy of inflammatory bowel diseases - aloin and aloe emodin. They are characterized first by a series of QSPR methods that calculate their lipophilicity, solubility, human intestinal absorption, oral bioavailability and the percentage of binding to plasma proteins, and then by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography that show the hydrophobicity of the analyte, high-performance liquid chromatography with a stationary phase containing immobilized artificial membranes showing lipophilicity, then with a stationary phase containing immobilized human serum albumin and finally one containing immobilized α1-acid glycoprotein to obtain the analyte binding affinity for HSA and AGP. In the end, it was shown that aloe emodin is more hydrophobic than aloin, is less soluble in water, has greater absorption in the intestine as well as oral bioavailability, and binds with greater affinity to plasma proteins compared to aloin. At the same time, deviations between different QSPR calculations are very big, and the most reliable pharmacokinetic properties remain to be investigated by in vitro methods.

• Keywords: aloin; aloe emodin; biomimetička kromatografija; upalne bolesti crijeva
• Keywords (english): aloin; aloe emodin; biomimetic chromatography; inflammatory bowel diseases
• Language: croatian
• URN:NBN: urn:nbn:hr:163:788096
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-04-11
• Created on: 2023-04-13 09:26:41