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Abstract
Background: Folic acid supplementation in patients with folic acid deficiency has been associated
with increased clearance of phenytoin to its cytochrome P450 (CYP) 2C9-mediated metabolite,
5-(4′-hydroxyphenyl)-5-phenylhydantoin.
Objective: The aim of this study was to determine whether folic acid supplementation increases
the dosage requirement of the CYP2C9 substrate warfarin, and the formation clearance
of the CYP2C9-mediated product, (S)-7-hydroxywarfarin.
Methods: Patients aged ≥18 years with folic acid deficiency who were receiving long-term treatment
with a stable dosage of warfarin were studied prospectively, before and 30 to 60 days
after the initiation of supplementation with folic acid. Warfarin dosage and international
normalized ratio (INR) were documented, and the formation clearance of (S)- and (R)-7-hydroxywarfarin and the oral clearance of (S)- and (R)-warfarin were determined.
Results: Twenty-four white patients (14 males; mean (SD) age, 55.0 [19.7] years; body mass
index, 30.64 [6.8] kg/m2) were enrolled. Treatment with folic acid was associated with a significantly increased
mean (SD) formation clearance of (S)-7-hydroxywarfarin (1.096 [0.816] vs 1.608 [1.302] mL/min; P = 0.048). Before folic acid supplementation, the mean (SD) warfarin dosage was 5.98
(2.12) mg/d, and the INR was 2.51 (0.55). During supplementation, the warfarin dosage
was 6.17 (2.31) mg/d and the INR was 2.63 (0.65) (both, P = NS vs before supplementation).
Conclusions: Folic acid supplementation was associated with significantly increased formation
clearance of (S)-7-hydroxywarfarin. Changes in warfarin dosage requirements and INR were nonsignificant.
Key words
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Article info
Publication history
Accepted:
November 23,
2009
Identification
Copyright
© 2010 Published by Elsevier Inc.
