5 research outputs found
NAT2 phenotype alters pharmacokinetics of rivaroxaban in healthy volunteers
Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs).
Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug
inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to
monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins
responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised
60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two
different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes
and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2)
and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under
fasting conditions presented lower tmax (2.21 h vs 2.88 h, β = 1.19, R2 =0.342, p = 0.012) compared to fed
volunteers. NAT2 slow acetylators presented higher AUC∞ corrected by dose/weight (AUC∞/DW; 8243.90 vs
7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R2 =0.250, p = 0.044), higher Cmax/DW (1070.99 vs 834.81
and 803.36 ng*mg /ml*kg, β = 0.245, R2 =0.320, p = 0.002), and lower tmax (2.63 vs 3.19 and 4.15 h, β =
− 0.346, R2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC∞
and Cmax. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban
pharmacokinetics and to determine its clinical significanceGonzalo Villapalos-García was co-financed by Instituto de Salud
Carlos III (ISCIII) and the European Social Fund (PFIS predoctoral grant,
number FI20/00090). Marcos Navares-Gomez ´ was financed by the
ICI20/00131 grant, Accion ´ Estrat´egica en Salud 2017–2020, ISCIII.
Pablo Zubiaur is financed by Universidad Autonoma ´ de Madrid,
Margarita Salas contract, grants for the requalification of the Spanish
university system. Paula Soria-Chacartegui is financed by Universidad
Autonoma ´ de Madrid (FPI-UAM, 2021). This study was co-financed by
Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF) “A way of making Europe”, number PI19/0093