Naslov
The importance of transporters in prediction of drug efficacy and adverse events

Autori
Božina, Nada ; Lovrić, Mila ; Ganoci, Lana

Vrsta, podvrsta i kategorija rada
Radovi u zbornicima skupova, cjeloviti rad (in extenso), znanstveni

Izvornik
2. Hrvatski simpozij o transporterima (SOT-2) / - , 2015

Skup
2. Hrvatski simpozij o transporterima s međunarodnim sudjelovanjem

Mjesto i datum
Zagreb, Hrvatska, 27.10.2015

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
drug transporters; genetic polymorphism; drug bioavailability; adverse drug reactions; drug- drug interactions

Sažetak
The important role of drug transporters in modulating pharmacokinetic and pharmacodinamic properties is documented for many drugs. Association studies between gene polymorphisms of the members of efflux transporters belonging to the ATP-binding cassette (ABC) superfamily of membrane proteins, as well as influx transporters of SLC superfamily, with the therapy response and clinical outcomes have been undertaken. Some convincing results have been obtained for ABCB1 gene variants and variability of therapy by digoxin, HIV protease inhibitors, some antiepileptics, antidepressants, antipsychotics, immunosuppressants ; ABCC2 and mycophenolic acid, anticancer drugs like methotrexate, cisplatin, irinotecan, antibiotics ; ABCG2 and anticancer drugs, statins, alopurinol, cimetidin, lamotrigin. The drug-drug interactions on the level of variable drug metabolism by phase I and phase II enzymes and drug transporters often called phase III, at many barrier tissues such as the intestine, liver, blood-brain barrier, kidney, placenta, modulate plasma and cerebrospinal fluid drug concentrations that can lead to the nonresponsiveness, resistance or serious even lethal adverse drug reactions. Most prominent case is development of rhabdomyolisis by statin therapy in case of variant/ineffective allele carriers of SLCO1B1 521C>T with aggravating role of ABCG2 421C>A and some CYP450 gene polymorphisms. Data also underlay the role of ABCB1 and ABCG2 polymorphisms as promising predictors of the clinical outcome of tyrosine kinase inhibitions (TKIs) therapy with drugs like imatinib, nilotinib, and sunitinib. Based on clinical evidence of drug transporter - mediated drug-drug interactions (DDIs) and some functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of transporters mediated DDIs. Although variability of bioavailability and drug response may be attributed to certain polymorphisms in transporter genes, transcriptional regulation or post- transcriptional modification seems to be even more critical in certain cases.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA