Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease.
1. Methylenetetrahydrofolate reductase (MTHFR) is a regulating enzyme in folate-dependant homocysteine remethylation, because it catalyses the reduction of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). 2. Subjects homozygous for the 677C --> T mutation in the MTHFR enzyme suffer from an increased cardiovascular risk. It can be speculated that the direct administration of 5-MTHF instead of folic acid can facilitate the remethylation of homocysteine in methionine. 3. The aim of this study was to determine the pharmacokinetic properties of orally administered 6[R,S] 5-MTHF versus folic acid in cardiovascular patients with homozygosity for 677C --> T MTHFR. 4. This is an open-controlled, two-way, two-period randomised crossover study. Patients received a single oral dose of either 5 mg folic acid or 5 mg 5-MTHF in each period. The concentrations of the 6[S] 5-MTHF and 6[R] 5-MTHF diastereoisomers were determined in venous blood samples. 5. All pharmacokinetic parameters demonstrate that the bioavailability of 5-MTHF is higher compared to folic acid. The peak concentration of both isomers following the administration of 6[R,S] 5-MTHF is almost seven times higher compared to folic acid, irrespective of the patient's genotype. However, at 1 week after the administration of a single dosage 6[R,S] 5-MTHF, we detected 6[R] 5-MTHF following the administration of folic acid, indicating storage of this isomer in the body. 6. Our results demonstrate that oral 5-MTHF has a different pharmacokinetic profile with a higher bioavailability compared to folic acid, irrespective of the patient's genotype. Detrimental effects of the storage of high levels of the non-natural isomer 6[R] 5-MTHF cannot be excluded.
Willems
Frank F
FF
Department of Cardiology, Rijnstate Hospital, PO Box 9555, Arnhem, 6800 TA, The Netherlands. fwillems@alysis.nl
Boers
Godfried H J
GH
Blom
Henk J
HJ
Aengevaeren
Wim R M
WR
Verheugt
Freek W A
FW
D000368:Aged; D001682:Biological Availability; D003324:Coronary Artery Disease / Q000378:metabolism*; D018592:Cross-Over Studies; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013763:Tetrahydrofolates / Q000097:blood / Q000493:pharmacokinetics*
D013763:Tetrahydrofolates; D005492:Folic Acid; C005984:5-methyltetrahydrofolate