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Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.Statini i nesteroidni protuupalni lijekovi (NSAID) učestalo se propisuju, pa i kao konkomitantna terapija. Postoji značajna interindividualna razlika u osjetljivosti na njihove najčešće nuspojave. Rizični čimbenici za razvoj nuspojava tih lijekova mogu biti povezani s lijekom i pacijentom ili s vanjskim čimbenicima. Polifarmacija je česta u kroničnih bolesnika i povećava rizik od razvoja interakcija lijekova. Istodobna primjena lijekovima koji inhibiraju CYP, UGT, ABC i / ili SLC prijenosnike lijekova (ABCB1, ABCG2 i OATP1B1) povezana je s produljenjem bioraspoloživosti lijekova, što rezultira povećanim rizikom od razvoja nuspojava. S tim u vezi, predstavljamo slučaj 46-godišnje žene koja je tijekom dvije godine doživjela akutno oštećenje bubrega i jetre, kao i mialgiju, dok je uzimala diklofenak, atorvastatin, fiksnu kombinaciju simvastatina / fenofibrata istovremeno s nekoliko drugih lijekova, uključujući pantoprazol i furosemid. Analiza dobivenih farmakogenetičkih rezultata te pregled dosadašnjeg znanja u tom području upućuju na zaključke da interakcije lijek-lijekgen mogu produljiti bioraspoloživost primijenjenih lijekova. Mehanizam se argumentirano temelji na sporijoj sposobnosti detoksikacije i smanjenoj eliminaciji putem jetre i bubrega, što rezultira toksičnošću za više organa. Jednako tako, prikazuje se važnost polimorfizama CYP u biotransformaciji endogenih supstrata poput arahidonske kiseline i u njihovoj modulacijskoj ulozi u patofiziološkim procesima. Danas postoje prilično značajni znanstveni dokazi o određenim farmakogenetičkim spoznajama koji rezultiraju povećanim rizikom od razvoja nuspojava za spomenute lijekove, no unatoč tomu, farmakogenetička analiza prije uvođenja lijekova u terapiju još nije uvedena u redovitu kliničku praksu.

Direktni oralni antikoagulansi (DOAK) posljednjih su godina pokazali rastući trend propisivanja zbog povoljne farmakokinetike i farmakodinamike bez potrebe za rutinskim nadzorom koagulacije. Svoj antikoagulantni učinak ostvaruju izravnom inhibicijom trombina (dabigatran) ili izravnom inhibicijom aktiviranog čimbenika X (rivaroksaban, apiksaban i edoksaban). Iako DOAK-i stupaju u manje interakcija s drugim lijekovima u usporedbi s varfarinom, kombinacija DOAK-a i mnogih lijekova zahtijeva oprez te u nekim slučajevima i klinički nadzor. Nedavne studije dokumentirale su interindividualnu varijabilnost u razinama DOAK-a u plazmi i odgovoru pacijenta na lijek. Iako klinički i biokemijski čimbenici mogu dovesti do interindividualnih varijabilnosti prisustvo genskih varijanti ili interakcije lijekova mogu doprinijeti tim razlikama. Potrebno je razumjeti ulogu farmakogenomike prvenstveno polimorfizam gena metaboličkih enzima i prijenosnika lijekova u interindividualnoj varijabilnosti četiri najčešće propisivana DOAK-a. Cilj istraživanja: Pregledno prikazati kako farmakogenetička predispozicija, prvenstveno polimorfizmi gena CYP3A4/5 i CES1, koji kodiraju metaboličke enzime, te ABCB1 i ABCG2, koji kodiraju transportne proteine, uz interakcije lijekova u politerapiji mogu doprinijeti interindividualnoj varijabilnost razina DOAK-a u plazmi, te učinkovitosti i sigurnosti njihove primjene. Materijali i metode: Prilikom izrade ovog rada provedena je opsežna pretraga nedavno objavljenih izvornih i preglednih znanstvenih radova, kliničkih ispitivanja, in vitro studija, terapijskih smjernica i publikacija stručnih društava. Naglasak je na polimorfizmima farmakogena bitnih za farmakokinetiku DOAK-a: gena CYP3A4/5 i CES1, za enzime uključene u biotransformaciju, te gena ABCB1 i ABCG2, za transportere lijekova i njihovom doprinosu u interindividualnoj varijabilnosti i bioraspoloživosti DOAK-a, te rizicima razvoja neželjenih učinaka prvenstveno krvarenja. Pretražena je baza podataka PubMed, Web of Science, Cochrane, Google Schoolar koristeći ključne riječi: apiksaban, CES1, CYP3A4, CYP3A5, dabigatran, direktni oralni antikoagulansi, edoksaban, farmakogenetika, farmakogenomika, genske varijante, interakcije gen-lijek, interakcije lijek-lijek, 4 krvarenje, novi oralni antikoagulansi, polimorfizam gena transportera ABCB1, ABCG2, rivaroksaban, SNP, tromboembolijski događaji u razdoblju od zadnjih 10-ak godina. Prikazani su interesantni slučajevi pacijenata iz kliničke prakse koji su zbog farmakogenetičke predispozicije i interakcije lijekova razvili nuspojave DOAK-a u vidu krvarenja. Raspravljene su prisutne dileme, te predočeno trenutno stanje u Hrvatskoj uspoređeno sa situacijom u Europi i drugdje u svijetu. Rezultati: Nekoliko varijanti gena CES1 i ABCB1 se smatra potencijalno odgovornim za nastanak interindividualnih varijabilnosti DOAK-a. Utvrđeno je da su varijante gena CES1 rs2244613 i rs8192935 povezane s nižim trough koncentracijama dabigatrana i nižim rizikom od krvarenja. S druge strane varijanta gena ABCB1 rs1045642 povezuje s povećanim vršnim koncentracijama dabigatrana i rivaroksabana, te povećanom učestalošću krvarenja. Farmakogenetička analiza varijanti gena ABCB1 rs2032582 (C.2677G> T) i rs104562 (C3435C> T) mogla bi biti opravdana i od koristi kod pacijenata na terapiji rivaroksabanom. Da bi se spriječili neželjeni učinci tijekom terapije apiksabanom kod nositelja nefunkcionalnih alela gena CYP3A5 potrebano je pažljivo odabrati dozu i pratiti nuspojave. Postoji veliki rizik od razvoja neželjenih učinaka lijeka kad se edoksaban kombinira s lijekovima koji inhibiraju CYP izoenzime u homozigotnih nositelja nefunkcionalnih alela za gen CYP3A5. Zaključak: Polimorfizam gena zajedno s istovremenom primjenom inhibitora/induktora transportnih proteina ili enzima odgovornih za metabolizam lijeka može povećati rizik od nastanka štetnih događaja vezanih uz promjenu DOAK-a. Due to good pharmacokinetics and pharmacodynamics without the requirement for routine coagulation monitoring, direct oral anticoagulants (DOAK) have seen an increase in prescribing in recent years. DOAC achieves its anticoagulant effect by direct inhibition of thrombin (dabigatran) or direct inhibition of activated factor X (rivaroxaban, apixaban and edoxaban). Although DOACs interact less with other drugs compared to warfarin, the combination of DOAC and many drugs requires caution and clinical supervision in some cases. Recent studies have documented interindividual variability in DOAC plasma levels and patient response to the drug. Although clinical and biochemical factors may lead to interindividual variability, the presence of genetic variants or drug interactions may contribute to these differences. The role of pharmacogenomics, namely polymorphism of metabolic enzyme genes and drug transporters, in the interindividual variability of the four most often prescribed DOACs, must be understood. Objectives: Demonstrate how pharmacogenetic predisposition, primarily polymorphisms of CYP3A4 / 5 metabolic enzyme genes, and CES1 and ABCB1 and ABCG2 transport proteins with drug interactions in polytherapy, may contribute to interindividual variability in DOAC plasma levels, and their efficiency and safety. Materials and methods: During the preparation of this paper, an extensive search of recently published original and reviewed scientific papers, clinical trials, in vitro studies, therapeutic guidelines and publications of professional societies was conducted. The emphasis is on pharmacogen polymorphisms that are important for DOAC pharmacokinetics: CYP3A4 / 5 and CES1 genes, for enzymes involved in biotransformation, and ABCB1 and ABCG2 genes, for drug transporters and their contribution to interindividual variability and bioavailability of DOACs, effects primarily of bleeding. The database PubMed, Web of Science, Cochrane, Google Schoolar were searched using keywords: apixaban, CES1, CYP3A4, CYP3A5, dabigatran, direct oral anticoagulants, edoxaban, pharmacogenetics, pharmacogenomics, gene variants, drug-drug interactions, gene-drug interactions, bleeding, new oral anticoagulants, polymorphism of transporter genes ABCB1, ABCG2, rivaroxaban, SNP, thromboembolic events in the period of the last 10 years. Interesting cases of patients from clinical practice who have developed DOAC side effects in the form of bleeding due to pharmacogenetic predisposition and drug interactions are presented. The present dilemmas were discussed, and the current situation in Croatia was compared to the situation in Europe and elsewhere in the world. Results: Several variants of the CES1 and ABCB1 genes are thought to be potentially responsible for the occurrence of interindividual variability in DOAC. Variants of the CES1 rs2244613 and rs8192935 genes were found to be associated with lower trough out dabigatran concentrations and a lower risk of bleeding. On the other hand, the ABCB1 gene variant rs1045642 is associated with increased peak concentrations of dabigatran and rivaroxaban, and increased bleeding frequency. Pharmacogenetic analysis of the ABCB1 gene variants rs2032582 (C.2677G>T) and rs104562 (C3435C>T) could be justified and useful in patients on rivaroxaban therapy. To prevent side effects during apixaban therapy in carriers of non-functional alleles of the CYP3A5 gene, the dose should be carefully selected and adverse reactions monitored. There is a high risk of developing adverse drug reactions when edoxaban is combined with drugs that inhibit CYP isoenzymes in homozygous carriers of non-functional alleles for the CYP3A5 gene. Conclusion: Gene polymorphism in combination with the concomitant use of inhibitors / inducers of transport proteins or enzymes responsible for drug metabolism may increase the risk of adverse events associated with alterations in DOACs.

Individual variation in response to drugs is an important clinical problem, which ranges from failure to respond to the drug, over adverse reactions to drugs, to interactions among drugs being administered concurrently. Numerous findings indicate that the differences in the patients response on the same drug are caused by genetic variations. This is the subject of pharmacogenetics. Although pharmacogenetics generally equated with the concept of pharmacogenomics, pharmacogenetics is primarily related to variations in a single gene that influence the on drug response, while pharmacogenomics is a broader term, which studies how all of the genes (the genome) can influence responses to drugs. In focus of this paper will be individual variation in response to drugs arising from single nucleotide polymorphisms in genes encoding the drug target proteins, enzymes that metabolize drugs, drug transporters, and polymorphisms of genes responsible for toxicity and hypersensitivity to drugs. Determination of pharmacogenetic profile of patients could point out patients who are at increased risk of adverse drug effects (for which drug should be applied at lower doses or other drugs can be used) and those in which are likely to achieve the desired therapeutic effect, and so to enable individualization of therapy. Individualne varijacije u odgovoru na lekove važan su klinički problem i mogu dovesti do potpunog odsustva reakcije na lek i pojave neželjenih reakcija na lekove. Brojni nalazi ukazuju da su razlike u odgovoru bolesnika na isti lek uslovljene genetskim varijacijama, i predmet su istraživanja farmakogenetike. Iako se farmakogenetika uglavnom izjednačuje sa pojmom farmakogenomika, farmakogenetika se uglavnom odnosi na varijacije u jednom genu koje utiču na odgovor na lek, dok je farmakogenomika šira oblast, koja ispituje kako svi geni u genomu povezani sa metabolizmom određenog leka mogu uticati na odgovor na dati lek. U ovom radu prevashodno će biti opisane individualne varijacije u odgovoru na lekove koje nastaju usled jednonukletidnih polimorfizama u genima koji kodiraju ciljne proteine lekova, enzime koji metabolišu lekove, transportere lekova, kao i polimorfizmi gena koji su odgovorni za toksičnost i preosetljivost na lekove. Određivanje farmakogenetskog profila bolesnika moglo bi da ukaže na bolesnike koji su u povećanom riziku od pojave neželjenih efekata lekova (kod kojih bi trebalo da se primene niže doze ili drugi lekovi) i na one kod kojih će se najverovatnije postići željeni terapijski efekat, odnosno da omogući individualizaciju terapije.

Farmakogenetika je disciplina koja proučava interindividualne razlike u slijedu DNA, a koje dovode do varijabilnog odgovora na terapiju lijekovima. Krajnji cilj farmakogenetike jest uspostava liječenja na principima tzv. personalizirane medicine, u kojoj se svakoj osobi, odnosno bolesniku, pristupa kao pojedincu. Način na koji se to postiže je da mu se metodama molekularne dijagnostike odredi farmakogenetski status i tako pruži mogućnost prilagodbe liječenja po njegovoj mjeri. Cilj ovog rada je sustavno prikazati ažurne informacije i smjernice farmakogenetskih principa liječenja, približiti ih i učiniti dostupnima kliničarima i drugim korisnicima, te tako potaknuti širu upotrebu farmakogenetike u kliničkoj praksi. Poseban naglasak je stavljen na kliničku interpretaciju smjernica na kojima se temelji odabir i doziranje lijekova s varijabilnim učinkom i nuspojavama, a koje ovise o rezultatu farmakogenetskog testiranja. Osim sustavnog prikaza smjernica iz relevantnih izvora koje su danas dostupne i primjenjive te prikaza potencijala farmakogenetike i farmakogenomike u fazama razvoja lijeka, načinjen je i kritički osvrt farmakogenetskih načela s obzirom na ograničenja koja otežavaju njihovo uvođenje u kliničku praksu. Među tim ograničenjima su cijena molekularnih testova, njihova relativna nedostupnost te složenost interpretacija rezultata. Ovaj je rad osnova za u skoroj budućnosti planiranu izradu web stranice – priručnika na hrvatskom jeziku, koja bi kliničarima i drugim zainteresiranim korisnicima omogućila jednostavniji pristup informacijama o farmakogenetskim načelima liječenja te dostupnosti pojedinih pretraga. U zaključku, farmakogenetika i farmakogenomika pružaju velike mogućnosti za poboljšanje kvalitete zdravstvene skrbi za svakog bolesnika. Međutim, one imaju smisla dok su ekonomski isplative, tj. određivanje terapeutskog profila ne prelazi financijska sredstva koja bi bila utrošena korištenjem konvencionalnih terapeutskih postupaka. Pharmacogenetics is a discipline that studies interindividual differences in DNA which cause a variable drug therapy response. The ultimate goal of pharmacogenetics is the establishment of treatment on the principles of so-called Personalized medicine, in which every person or patient is managed as an individual. The way in which it is achieved - is to determine its pharmacogenetic status by molecular diagnostic methods and thus provide the possibility of adjusting the treatment to each patient’s needs. The aim of this paper is to systematically present pharmacogenetic principles up-to-date information and treatment recommendations, to make them available to clinicians and other users, thus promoting the use of pharmacogenetics in clinical practice. Particular emphasis has been put on the clinical interpretation of the guidelines which are the basis of drug choice and dosage, with variable outcomes and side effects that depend on the pharmacogenetic testing result. In addition to a systematic overview of the relevant sources available and applicable today, as well as the pharmacogenetics and pharmacogenomic potential in drug development phases, a critical review of the pharmacogenetic principles has been made, with regard to the constraints that make them difficult to be introduced into clinical practice. Among these limitations are the price of molecular tests, their relative inaccessibility, and the complexity of the interpretation of results. This work is the basis for the construction of a Croatian language website - manual in the near future, which would provide easier access to information on pharmacogenetic treatment principles and specific tests availability to clinicians and other interested users. In conclusion, pharmacogenetics and pharmacogenomics provide great opportunities to improve the quality of health care for each patient. However, they make sense while being economically viable, i.e. determining a therapeutic profile does not exceed the financial resources that would be spent using conventional therapeutic procedures.

Razvoj nove discipline farmakogenetike/farmakogenomike omogućio je bolje razumijevanje genetičke predispozicije za razvoj neočekivanih reakcija na primijenjeni lijek i posljedično unaprijedio individualizaciju farmakoterapije. Postoje genetički određene interindividualne razlike u metaboličkom i transportnom kapacitetu, a time i kinetici lijekova i drugih ksenobiotika. Osim nuspojava lijekova koje su ovisne o dozi važne su nuspojave posredovane imunosnim reakcijama, a povezane su s varijabilnosti u sustavu HLA. Individualna osjetljivost prema toksičnim učincima farmakoterapije, ovisna o biotransformacijskim procesima, povezuje se s genskim polimorfizmima enzima faze I. i II. te transporterima ABC i SLC. Genski polimorfizmi također mogu imati ključnu ulogu u interakcijama lijekova. Povezivanje farmakogenomike s farmakovigilancijom ima važnu ulogu i u praćenju pojavnosti nuspojava poslije stavljanja lijeka na tržište. Regulatorna tijela uvođenjem farmakogenomičkih informacija (informacije o genomskim biljezima) u Sažetku o proizvodu (SPC) nastoje istaknuti ulogu i važnost genomskih varijabilnosti u farmakoterapiji. Također se navodi kojoj kategoriji te farmakogenetičke informacije pripadaju, tj. smatra li se testiranje obvezatnim, ima li ulogu preporuke ili je informativnog karaktera. Radi prikupljanja i implementacije znanja ustanovljeni su i različiti konzorciji među kojima prednjači Clinical Pharmacogenetics Implementation Consortium – CPIC, kao zajednički projekt The Pharmacogenomics Knowledge Base (PharmGKB) i The Pharmacogenomics Research Network koji je okupio eminentne stručnjake iz područja farmakogenetike/farmakogenomike. Glavni je cilj CPIC-a izdavanje recenziranih, ažuriranih, temeljenih na dokazima, slobodno dostupnih uputa i smjernica za primjenu lijeka prema rezultatu farmakogenetičkih analiza. Te će smjernice svakako ubrzati prijenos znanja u kliničku primjenu., The development of a new discipline, pharmacogenetics/pharmacogenomics, has enabled a better understanding of genetic predispositions for unexpected drug reaction developments, and consequently it improves the individualization of pharmacotherapy. There are certain genetic individual variations in metabolic and transport capacity, and thus the kinetics of drugs and other xenobiotics. In addition to adverse drug reactions (ADR) that are dose-dependent, significant ADR are mediated by immune reactions and are associated with variations in the HLA system. The individual sensitivity to the pharmacotherapy toxic effects, dependent on biotransformation processes, is associated with the genetic polymorphism of the phase I and phase II enzymes and ABC and SLC transporters. Genetic polymorphisms can also play a key role in drug interactions. Connecting pharmacogenomics to pharmacovigilance has a significant role in monitoring ADR during the post-marketing period. Regulatory authorities highlight the role and importance of genomic variability in pharmacotherapy by introducing pharmacogenomics (information on genomic markers) in the SPC. It also states into which category pharmacogenetics information belongs, whether pharmacogenetic testing is required, recommended or informative. In order to collect and implement pharmacogenomic knowledge different consortia have been established, including prestige Clinical Pharmacogenetics Implementation Consortium (CPIC), as a joint project of The Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network, which brought together eminent experts in the field of pharmacogenetics/pharmacogenomics. The main objectives of CPIC’s is to provide peer-reviewed, updated, evidence-based, freely available recommendations and guidelines for drug use according to results of pharmacogenetic analysis. These guidelines will certainly accelerate the knowledge transfer to the clinical use.

Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac., Interindividualne razlike u metabolizmu mogu biti važan čimbenik nastanka nuspojava te varijabilnosti u učinkovitosti lijeka. Polimorfizmi gena koji kodiraju metaboličke enzime citokrome P450 (CYP) mogu imati značajan učinak na metabolizam lijeka i toksičnost. Ovaj pregled donosi spoznaje o tome kako polimorfizam enzima CYP2C8 i CYP2C9 utječe na bioraspoloživost i kliničke ishode liječenja ibuprofenom i diklofenakom, koji se svrstavaju među najčešće propisivane nesteroidne protuupalne lijekove. Hepatotoksičnost i gastrointestinalno krvarenje najčešće su nuspojave povezane s utjecajem varijanti CYP2C8*3 i CYP2C9*2*3 na farmakokinetiku ibuprofena i diklofenaka. Na osnovi rezultata genotipizacije CYP-a mogu biti prepoznati pacijenti koji imaju povećani rizik od razvoja nuspojava te im je nužno prilagoditi dozu lijeka ili odabrati drugi lijek koji ne dijeli isti metabolički put. Osim enzima CYP, značajan utjecaj imaju i polimorfizmi gena koji kodiraju fazu II metabolizma, osobito enzimi UGT, te transporteri, poput ABCC2, koji mogu modulirati ne samo transport na barijeri jetre i žuči nego i izlučivanje bubrezima. Stoga je u budućim istraživanjima nužan poligenski pristup. Prije uvođenja genotipizacije u redovitu kliničku praksu potrebno je provesti daljnja istraživanja koja će uključivati veće fenotipski dobro definirane skupine ispitanika za procjenu učinkovitosti ove strategije u poboljšanju liječenja ibuprofenom i diklofenakom. Zbog značajne međuetničke razlike u učestalosti polimorfizama gena CYP istraživanja treba provesti među različitim rasama i populacijama.

Cilj istraživanja Cilj ovoga specijalističkoga rada je prikupiti, kroz pretraživanje znanstvene i stručne literature, i kritički procijeniti relevantne podatke koji se odnose na utjecaj genskih varijanti onih gena čiji proteinski produkti utječu na učinkovitost terapije statinima. Materijali i metode Tijekom izrade i pisanja ovoga specijalističkoga rada sustavno je pretražena znanstvena i stručna literature iz područja farmakogenetike, farmakogenomike, farmakoterapije i kardiologije, kako domaća tako i strana. Kao literaturni izvori korišteni su i odgovarajući priručnici, knjige i udžbenici koji se kao nastavna literatura koriste na studijima medicine i farmacije. Za detaljniji opis pojedinih lijekova iz skupine inhibitora hidroksi-metil-glutaril-koenzim-A-reduktaze korišteni su podaci iz Sažetka opisa svojstava lijeka te baze interakcija Lexicomp i Drugs.com. Od dostupnih baza podataka pretraživane su baze podataka Medline i PubMed za ključne riječi: inhibitori hidroksi-metil-glutaril-koenzim-A-reduktaze, statini, farmakogenetika, farmakogenomika, genski polimorfizam. Zaključak Do danas je identificirano više gena čiji proteinski produkti imaju utjecaja na farmakokinetiku i farmakodinamiku statina. Za kliničku praksu najznačajnije su varijante (polimorfizmi) onih gena koji kodiraju proteine uključene u farmakokinetiku statina tj. apsorpciju, distribuciju, metabolizam i izlučivanje, a to su enzimi iz porodice CYP-a, P-glikoprotein i organski anionski transportni polipeptid (OATP). Lovastatin, atorvastatin i simvastatin se najviše metaboliziraju putem CYP3A4 i CYP3A5, a fluvastatin putem CYP2C9 i CYP2C8. Metabolizam ovih lijekova može biti djelomično posredovan i putem CYP2D6 ili nekoliko glukuronozil-transferaza (UGT1A1, UGT1A3, UGT2B7). Pravastatin i rosuvastatin imaju minimalnu interakciju s metaboličkim enzimima i uglavnom se izlučuju nepromijenjeni. Zbog toga se smatra da su pravastatin i rosuvastatin najmanje pod utjecajem genskih varijacija metaboličkih enzima. Kod pacijenata koji su na politerapiji značajno se povećava vjerojatnost neželjenih interakcija lijekova, posebice u slučajevima onih pacijenata koji su zbog genskih polimorfizama spori ili vrlo brzi metabolizatori. Ako se kod takvih pacijenata istovremeno sa statinima primjenjuju i lijekovi koji su inhibitori ili induktori enzima iz obitelji CYP-a, mogućnost nuspojava i toksičnosti značajno raste. Polimorfizam 3435T na MDR1 ili ABCB1 genu povezan je sa smanjenom ekspresijom P-glikoproteina. Inhibicija i indukcija P-glikoproteina je novije otkriven mehanizam koji utječe na interakcije lijekova. Osobe koje su nositelji T/C ili C/C genotipa kod polimorfizma gena SLCO1B1 (rs4149056 (521T>C)) imaju lošiji odgovor na terapiju statinima te imaju veći rizik za razvoj nuspojava za razliku od osoba koji su nositelji T/T genotipa. Genski polimorfizmi koji imaju utjecaj na farmakodinamiku statina od manjeg su kliničkog značaja. Poznavanje genskih polimorfizama ne može apsolutno prognozirati kako će pacijent reagirati na propisanu terapiju, ali može biti dobar putokaz za opreznije doziranje pojedinih lijekova i učestalije praćenje rizičnih pacijenta. Objectives The aim of this work is to search the literature and collect a large number of data for assesment of the impact of gene polymorphisms of the genes whose protein products influence the effectiveness of statin therapy. Materials and Methods During the writing and preparation of this thesis, literature by Croatian and foreign authors in the fields of pharmacogenetics, pharmacogenomics, pharmacotherapy and cardiology was systematically reviewed. Manuals, books and textbooks, which are used in studies of pharmacy and medicine were also used. For a more detailed description of certain drugs from the group of inhibitors of hydroxy-methyl-glutaryl-coenzyme-A-reductase, data from the SPC, and base interaction Lexicomp and Drugs.com were used. From available databases, the databases Medline and PubMed were searched for the following keywords: hydroxy-methyl-glutaryl-coenzyme-A-reductase inhibitors, statins, pharmacogenetics, pharmacogenomics, gene polymorphism. Conclusion Several genes whose protein products may affect pharmacokinetics and pharmacodynamics of statins have beeen identified so far. In clinical practice, it is the variants (polymorphisms) of genes that encode proteins involved in the pharmacokinetics of statins , i.e. , absorption, distribution, metabolism and excretion, that are the most important. They are enzymes of the CYP family, P-glycoprotein and organic anion transporting polypeptide (OATP). Lovastatin, atorvastatin and simvastatin are mostly metabolised by cytochrome CYP3A4 and CYP3A5, and fluvastatin through CYP2C9 and CYP2C8. The metabolism of these drugs may be partially mediated through the CYP2D6 or several glucuronosyltransferase (UGT1A1, UGT1A3, UGT2B7). Pravastatin and rosuvastatin have minimal interaction with metabolic enzymes and are mainly excreted unchanged. Therefore, it is considered that pravastatin and rosuvastatin are least affected by genetic variations of metabolic enzymes. In patients with polytherapy the possibility of drug interactions increases significantly, especially in the case of patients who are, due to genetic polymorphism, slow or very fast metabolizers. If inhibitors or inducers of CYP enzymes are coadministrated with statins, the possibility of side effects and toxicity increases significantly. 3435T polymorphism of the MDR1 (ABCB1) gene is associated with reduced expression of P-glycoprotein. Inhibition and induction of P-glycoprotein is a recently discovered mechanism that may affect drug interactions. People who are carriers of the T/C or C/C genotype of SLCO1B1 gene polymophysm (rs4149056 (521T>C)) have a poorer response to therapy with statins, and are at greater risk of developing side effects than carriers of the T/T genotype. Genetic polymorphisms that have an impact on pharmacodinamics of statins are clinically less significant. Knowledge of the genetic polymorphisms can not absolutely predict how a patient will respond to prescribed therapy, but can be a good indicator of the need for cautious dosage of certain drugs and frequent monitoring of patients at risk.

Mercaptopurine (6-mercaptopurine) together with azathioprine and 6-thioguanine belong to a group of widely used chemotherapeutics and immunosuppressants. However, insufficient therapy outcome or severe adverse effects such as myelosuppression are still being reported. Technological progress in DNA and RNA sequencing facilitates effective identification of causative genes responsible for the therapy failure, i.e., description of genetic variants for enzymes involved in metabolism of physiological purines as well as thiopurine drugs. Variants of these enzymes may substantially alter concentrations of cytotoxic forms of thiopurines, which affect therapy success rates. Currently, a number of mutations in genes that play role in thiopurine metabolism have been annotated. Nevertheless, molecular mechanisms underlying the effect of these mutations are not fully elucidated. Knowledge of 3D structure for these enzymes may shed light on the effect of the genetic variants to protein function and mechanisms modulating therapeutic efficacy of thiopurines. This thesis focuses mainly on biochemical and structural characterization of thiopurine-S-methyltransferase, fosfatase NUDT15 and cytosolic 5′-nucleotidase II. It summarizes current state of knowledge and emphasizes the importance of structural biology methods for...

Farmakogenetika, a posebno farmakogenomika, nove su znanstvene discipline čiji početni rezultati daju nadu da će se među bolesnicima koji boluju od depresije uspjeti prepoznati homogene skupine s obzirom na očekivani terapijski odgovor i na taj način omogućiti učinkovitije liječenje depresije. Sasvim je jasno da je terapijski odgovor rezultat složenih genskih učinaka, a ne samo jednoga gena. Na njega utječu ne samo genski polimorfizmi nego i varijacije u ekspresiji gena i posttranslacijske modifikacije proteina pod utjecajem brojnih čimbenika kao što su doza lijeka, prehrana te interakcije s drugim tvarima unijetim u organizam. Ne valja očekivati da bi se samim farmakogenetičkim ili čak farmakogenomskim istraživanjima mogla objasniti većina varijabiliteta u terapijskom odgovoru, no ustanovljavanje uzroka čak i dijela njegova varijabiliteta koji je pod izravnim genskim utjecajem znatno bi pridonijelo pouzdanijoj procjeni očekivanog terapijskog učinka i značajnije povisilo sada nizak udio bolesnika koji povoljno odgovaraju na antidepresivnu terapiju. Veći dio varijabiliteta terapijskog odgovora bit će moguće objasniti tek daljnjim razvojem transkriptomskih i proteomskih istraživanja koja su, za sada, ipak još u fazi ranog razvoja., Pharmacogenetics, and particularly pharmacogenomics, are new scientific disciplines whose initial results hold promise that the homogeneous groups with respect to the expected therapeutic response will be recognized among people suffering from depression, which would enable its more efficient treatment. It is clear that the therapeutic response is a result of complex genetic effects, and not only of one gene. Therapeutic response is affected not only by genetic polymorphisms, but also by variations in gene expression and post-translational modifications of proteins under the influence of numerous factors, e.g. dose, food, interactions with other substances. Although pharmacogenetic or even pharmacogenomic studies alone are not expected to completely elucidate the variability in the therapeutic response, the establishment of at least some causes of this variability, which is under a direct genetic influence, would significantly contribute to a more reliable assessment of expected therapeutic response and considerably increase a currently low share of patients responding to antidepressant therapies. For the most part, the variability in the therapeutic response can be explained only by further transcriptomic and proteomic research that is, currently, in the early phase of development.