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A New Algorithm for Weekly Phenprocoumon Dose Variation in a Southern Brazilian Population: Role for CYP 2C9, CYP 3A4/5 and VKORC 1 Genes Polymorphisms
Abstract Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non‐genetic factors. Phenprocoumon metabolism is mediated by CYP 2 C 9 and CYP 3 A enzymes. Moreover, VKORC 1 is ph...
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| Published in: | Basic & clinical pharmacology & toxicology 2014-04, Vol.114 (4), p.323-329 |
|---|---|
| Main Authors: | , , , , , |
| Format: | Article |
| Language: | English |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
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| Summary: | Abstract
Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non‐genetic factors. Phenprocoumon metabolism is mediated by
CYP
2
C
9 and
CYP
3
A
enzymes. Moreover,
VKORC
1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (
SNP
s) in
VKORC
1,
CYP
2
C
9,
CYP
3
A
4 and
CYP
3
A
5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of
E
uropean ancestry, were investigated. Genotypes were determined by allelic discrimination with
T
aq
M
an assays. Polymorphisms −1639G>A and 1173C>T in
VKORC
1 and the presence of
CYP
2
C
9*2 and/or
CYP
2
C
9*3 are associated with lower doses. On the other hand, 3730G>A in
VKORC
1 gene is associated with higher doses. No association was found between
CYP
3
A
4*1
B
,
CYP
3
A
5*3 and
CYP
3
A
5*6 polymorphisms. Among non‐genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and β‐blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm. |
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| ISSN: | 1742-7835 1742-7843 |
| DOI: | 10.1111/bcpt.12172 |