Objective To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase ( VKOR) and CYP2C9. Methods Warfarin maintenance dose, unbound plasma S-warfarin concentration [ Cu( S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset ( n=166), fully carboxylated plasma normal prothrombin levels ( NPT) were also measured. Genotyping for seven CYP2C9 ( CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement. Results The relationship between NPT and Cu( S) indicated Japanese are more susceptible to inhibition of NPT production by S- warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese ( 89.1%) than Caucasians ( 42.2%) and African-Americans ( 8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients ( 5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype- matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (* 2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage. Conclusions Both VKORC1 and CYP2C9 polymorphisms contribute to inter- population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.

Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans.

PENGO, V;PADRINI, ROBERTO;
2006

Abstract

Objective To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase ( VKOR) and CYP2C9. Methods Warfarin maintenance dose, unbound plasma S-warfarin concentration [ Cu( S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset ( n=166), fully carboxylated plasma normal prothrombin levels ( NPT) were also measured. Genotyping for seven CYP2C9 ( CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement. Results The relationship between NPT and Cu( S) indicated Japanese are more susceptible to inhibition of NPT production by S- warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese ( 89.1%) than Caucasians ( 42.2%) and African-Americans ( 8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients ( 5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype- matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (* 2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage. Conclusions Both VKORC1 and CYP2C9 polymorphisms contribute to inter- population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.
2006
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/139034
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