Naslov
Pharmacogenetics and adverse drug reactions - polymorphism of metabolic enzymes

Autori
Božina, Nada ; Čuković-Čavka, Silvija ; Šupe, Svjetlana ; Nađ-Škegro, Sandra ; Šimić, Iveta ; Makar-Aušperger, Ksenija ; Kovačević, Ivana

Izvornik
Neurologia Croatica (0353-8842) 61 (2012), Suppl 2; 121-132

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
adverse drug reactions; CYP2C19; CYP2C9; CYP2D6; CYP3A4/5; drug metabolism; genetic polymorphism; NAT2; TPMT; UGT1A1

Sažetak
Adverse drug reactions (ADRs) are a significant problem resulting in substantial morbidity, mortality, and healthcare expenses. 90% of ADR are due to a medication that was properly administered. In addition, according to published data, ADRs are also responsible for up to 7% of hospitalizations - a number that increases to > 30% in the elderly population. Variability in drug response can be explained, in part, by genetic diff erences among patients. Th ere are interindividual diff erences in the capacity to metabolize and detoxify drugs and other xenobiotics. Th e individual susceptibility for toxicity is to some extent dependent on the genetic polymorphism of phase I and II metabolic enzymes. Clinically, the most important polymorphisms in phase I are of the CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 genes, and in phase II those are TPMT, UGT1A1, NAT2, SULTs. Th e most striking influence seen at present is the eff ects of the defective and rapid CYP2C19 alleles on the outcome of clopidogrel treatment, as well as severe adverse reaction in CYP2D6 ultrarapid metabolizers observed aft er codeine therapy. Another important eff ect has been observed in cases of nonresponsiveness to antidepressant therapy and suicides reported in subjects who were rapid metabolizers and side eff ects in poor metabolizers for CYP2D6. Patients carrying defective CYP2C9 alleles are under increased risk of overdosing with drug substrates that can lead to phenytoin intoxication, or bleeding in case of coumarin anticoagulants or nonsteroidal antiinflammatory drugs. Guidelines are available for TPMT geno typing in case of thiopurine drugs, as well as recommendations for UGT1A1 analysis for optimization of irinotecan therapy.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA