Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.

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 >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.

• Authors: Mordechai Muszkat, Omer Bialer, Simcha Blotnick, Liat Adar, Hong-Guang Xie, Mike Ufer, Ingolf Cascorbi, Yoseph Caraco
• Journal: Clinical therapeutics (Clin Ther) Vol. 32 Issue 2 Pg. 347-56 (Feb 2010) ISSN: 1879-114X [Electronic] United States
• PMID: 20206792 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010. Published by EM Inc USA.

Chemical References

• Anticoagulants
• Vitamin B Complex
• Warfarin
• Folic Acid
• 7-hydroxywarfarin
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Aryl Hydrocarbon Hydroxylases

Topics

• Administration, Oral
• Adult
• Aged
• Anticoagulants (administration & dosage, pharmacokinetics)
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Biotransformation
• Blood Coagulation (drug effects)
• Cytochrome P-450 CYP2C9
• Dietary Supplements
• Drug Interactions
• Female
• Folic Acid (administration & dosage, pharmacology)
• Genotype
• Humans
• International Normalized Ratio
• Male
• Metabolic Clearance Rate
• Middle Aged
• Phenotype
• Polymorphism, Genetic
• Prospective Studies
• Vitamin B Complex (administration & dosage, pharmacology)
• Warfarin (administration & dosage, analogs & derivatives, pharmacokinetics)