Abstract
The pharmacogenetics of warfarin in clinical practice
Highlights
In 2007, the Food and Drug Administration (FDA) announced that warfarin’s label will carry new information describing the role of genetics in drug dosing
The pharmacological e ect of warfarin is mediated by the inhibition of vitamin K epoxide reductase complex 1 (VKORC1)
Carriers of alleles coding for reduced CYP2C9 and/or VKORC1 enzyme activity require lower warfarin doses and have been observed to be more di cult to titrate to a stable maintenance dose than those needing higher doses
Summary
Postoje velike interindividualne razlike (i do 20 puta) u potrebnim dozama lijeka, što je rezultat genetičkih i okolišnih čimbenika. Podaci dobiveni analizom dvaju gena, enzima za metabolizam varfarina CYP2C9 i ciljnog enzima za varfarin, podjedinice 1 vitamin K ovisne epoksid reduktaze (VKORC1), potvrdili su njihov učinak na dozu održavanja varfarina. Jednonukleotidni polimor zmi VKORC1 objašnjavaju velik dio interindividualnih razlika u dozi varfarina, a VKORC1 ima otprilike tri puta jači učinak od CYP2C9. Stanje nositelja kombinacije polimor zama VKORC1 i CYP2C9 udruženo je s teškom prekomjernom antikoagulacijom. Vrijeme do postizanja stabilnosti doze uglavnom je povezano s genotipom CYP2C9. Otpornost na varfarin vezuje se za nekoliko missense mutacija u genu VKORC1. Algoritmi koji uključuju genetičke (CYP2C9 i VKORC1), demografske i kliničke čimbenike za procjenu doze varfarina mogli bi smanjiti rizik od predoziranja za vrijeme uvođenja varfarina
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