Terapijsko praćenje metabolita tiopurina u bolesnika s upalnim bolestima crijeva

master's thesis

• Title (english): Therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel disease
• Author: Iva Ćurić
• Mentor: Mila Lovrić (mentor)
• Committee member: Mila Lovrić (predsjednik povjerenstva)
• Committee member: Lidija Bach-Rojecky (član povjerenstva)
• Committee member: Maja Ortner Hadžiabdić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2020-09-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Tiopurini su imunosupresivni lijekovi korišteni u terapiji upalnih bolesti crijeva. Biotransformiraju se u inaktivne metabolite od kojih je najznačajniji 6-metilmerkaptopurin (6-MMP) te u aktivni citotoksični metabolit 6-tiogvaninski nukleotid (6-TGN) koji djeluje protuupalno. Enzim koji katalizira nastanak 6-MMP je tiopurin-S-metiltransferaza (TMPT), podložna genetskim polimorfizmima koji utječu na enizmatsku aktivnost. Osim genetskih polimorfizama TPMT, na koncentraciju 6-MMP i 6-TG utječu farmakokinetički i okolišni čimbenici. Cilj rada je odrediti koncentraciju metabolita tiopurina u krvi bolesnika s upalnim bolestima crijeva u stanju dinamičke ravnoteže, izračunati metilacijski indeks iz dobivenih koncentracija, utvrditi ovisnost koncentracija metabolita prije i nakon ujednačavanja prema dozi o dobi te procijeniti koncentracije metabolita prema terapijskom rasponu i indeksu metilacije. Koncentracije 6-TG i 6-MMP određene su HPLC metodom. U ispitivanje je uključeno 100 bolesnika s upalnim bolestima crijeva koji su na terapiji tiopurinima, starosti od 11 do najviše navršenih 65 godina. Regresijskom analizom utvrđeno je da ne postoji linearna ovisnost koncentracija metabolita tiopurina o dobi ispitanika. Zaključeno je da dob ne utječe na vrijednosti koncentracija metabolita u eritrocitima. Kod samo 1/3 bolesnika postignute su očekivane koncentracije aktivnog metabolita, 6-TG. S ciljem optimizacije režima doziranja i minimaliziranja nuspojava, terapijsko praćenje tiopurina trebalo bi biti rutinska metoda.

Abstract (english)

Thiopurines are immunosuppressive drugs used in the treatment of inflammatory bowel disease. They are metabolized into inactive metabolites, the most important of which is 6-methylmercaptopurine (6-MMP) and into the active cytotoxic metabolite 6-thioguanine nucleotide (6-TGN) which has an anti-inflammatory effect. The enzyme that catalyzes the formation of 6-MMP is thiopurine-S-methyltransferase (TMPT), susceptible to genetic polymorphisms that affect enzymatic activity. In addition to TPMT genetic polymorphisms, 6-MMP and 6-TG concentrations are influenced by pharmacokinetic and environmental factors. The aim of this study was to determine the concentration of thiopurine metabolites in the blood of patients with inflammatory bowel disease at steady state, to calculate the methylation index from the obtained concentrations, to determine the dependence of metabolite concentrations before and after dose adjustment, to evaluate metabolite concentrations according to therapeutic range and methylation index. Concentrations of thiopurine metabolites were determined by HPLC method. The study included 100 patients with inflammatory bowel disease who were on thiopurine therapy, aged 11 to a maximum of 65 years. Regression analysis showed that there is no linear dependence of thiopurine metabolite concentrations on the age of the subjects. It was concluded that age did not affect the values of metabolite concentrations in erythrocytes. In only 1/3 of patients, the expected concentrations of the active metabolite, 6-TG, were achieved. In order to optimize the dosing regimen and minimize side effects, therapeutic monitoring of thiopurine should be a routine method.

• Keywords: tiopurini; upalne bolesti crijeva; terapijsko praćenje; TMPT; 6-MMP; 6-TG
• Keywords (english): thiopurines; inflammatory bowel disease; therapeutic drug monitoring; TMPT; 6-MMP; 6-TG
• Language: croatian
• URN:NBN: urn:nbn:hr:163:213012
• 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: Open access
• Created on: 2021-11-15 16:41:13