Značenje reakcija biotransformacija u pojavi idiosinkratskih reakcija lijekova

professional thesis

• Author: Andrea Antolić
• Mentor: Mirza Bojić (mentor)
• Committee member: Milena Jadrijević-Mladar Takač (predsjednik povjerenstva)
• Committee member: Mirza Bojić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2016, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Osnovna podjela nuspojava na lijekove je na nuspojave tipa A koje nastaju kao posljedica pretjeranog farmakološkog učinka lijeka, te na nuspojave tipa B, odnosno idiosinkratske reakcije. Idiosinkratske reakcije su nepredvidive, odgođene u nastanku, niske učestalosti, ali velike smrtnosti. Čine 10% ukupnih nuspojava na lijekove i predstavljaju veliki problem s obzirom da su posljedice takvih reakcija često opasne po život, a sam mehanizam nastanka nije u potpunosti razjašnjen. Ispitivanja toksičnosti tijekom razvoja novih lijekova pokazala su se neučinkovita u predviđanju lijeka kandidata i njegove povezanosti s pojavom idiosinkratskih reakcija, što ponekad dovodi do povlačenja lijekova s tržišta ili stavljanja oznake upozorenja. Dosadašnja istraživanja pokazuju kako je biotransformacija lijekova u reaktivne metabolite često uzrokom nastanka idiosinkratskih reakcija, stoga postoji potreba za boljim razumijevanjem osnovnih mehanizama koji dovode do stvaranja reaktivnih metabolita. Idiosinkratske reakcije mogu zahvatiti bilo koji organ, no najčešće se manifestiraju na koži, jetri te koštanoj srži, a većina nastaje posredovanjem imunološkog sustava. Pregledom literature iz PubMed citatne baze primjenom ključnih riječi naziv lijeka i idiosinkratske reakcije, prikazani su karakteristični lijekovi i njihova biotransformacija u reaktivne metabolite prema mjestu nastanka idiosinkratske reakcije. Kako je malen broj prikladnih modela za ispitivanje mehanizama nastanka idiosinkratskih reakcija, prilikom razvoja novih lijekova potrebno je razviti strategije za predviđanje takvih reakcija. Moguće strategije su izbjegavanje funkcionalnih skupina koje su podložne biotransformaciji u reaktivne metabolite, praćenje kovalentnog vezanja potencijalnog lijeka za makromolekule ili glutation te pronalazak novih animalnih modela koji bi omogućili bolje razumijevanje mehanizma.

Abstract (english)

Adverse drug reactions (ADR) are conventionally classified into two types – type A reactions that are result of enhanced pharmacological effect, and type B reactions or idiosyncratic drug reactions. Idiosyncratic drug reactions are unpredictable, delayed in onset, low frequency but high mortality. Representing 10% of total ADRs, they remain a big problem considering that the consequences of such reactions are often life-threatening, and the mechanisms are not fully understood. Toxicity testing has been ineffective in the prediction of drug candidates that could be associated with a relatively high incidence of idiosyncratic drug reactions, which sometimes leads to the withdrawal of some drugs from the market or “black box” warnings for others. Previous studies have shown that the biotransformation of drugs to reactive metabolites are often cause of idiosyncratic drug reaction, therefore there is a need for better understanding of the basic mechanisms involved in the formation of reactive metabolites. Idiosyncratic drug reactions can affect any organ, but skin, liver, and bone marrow are the most common targets and most idiosyncratic drug reactions appear to be immune mediated. A literature search of PubMed citation database using the keywords drug and idiosyncratic drug reactions was used in this review. The paucity of animal models makes mechanistic studies very difficult to proceed, so there is a need to develop some screening methods for the idiosyncratic drug reactions. Possible strategies are avoiding functional groups that are susceptible to biotransformation to reactive metabolites, screening of covalent binding to proteins or formation of gluthatione conjugates, and finding new animal models which would allow better understanding of the mechanism.

• Keywords: nuspojave lijekova; idiosinkratske reakcije; reaktivni metaboliti; biotransformacija lijekova
• Keywords (english): adverse drug reacutions; idiosyncratic drug reactions; reactive metabolites; biotransformation of drugs
• Language: croatian
• URN:NBN: urn:nbn:hr:163:929421
• Study programme: Title: Drug development; Study programme type: university; Study level: postgraduate specialist; Academic / professional title: sveučilišni magistar/sveučilišna magistra razvoja lijekova (sveučilišni magistar/sveučilišna magistra razvoja lijekova)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2018-10-11 11:01:32