Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.
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 >or=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/m(2)) 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.
Muszkat
Mordechai
M
Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Bialer
Omer
O
Blotnick
Simcha
S
Adar
Liat
L
Xie
Hong-Guang
HG
Ufer
Mike
M
Cascorbi
Ingolf
I
Caraco
Yoseph
Y
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D001777:Blood Coagulation / Q000187:drug effects*; D065729:Cytochrome P-450 CYP2C9; D019587:Dietary Supplements; D004347:Drug Interactions; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology*; D014859:Warfarin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014803:Vitamin B Complex; D014859:Warfarin; D005492:Folic Acid; C087837:7-hydroxywarfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases