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.
Bibliographical noteFunding Information:
This research was financially supported by German-Israeli Foundation for Scientific Research and Development research grant no. I-2027-1086.2/00 and National Institutes of Health grant no. GM 31304.
- folic acid
- nutrient-drug interaction