Enhanced oral bioavailability of a novel folate salt: comparison with folic acid and a calcium folate salt in a pharmacokinetic study in rats

Minerva Ginecol. 2016 Apr;68(2):99-105.


Background: Folates play an important role to prevent neurological disorders in embryo development and in cardiovascular diseases. Folate supplementation is suggested, particularly in females of childbearing age, for the prevention of embryonal NTDs during pregnancy. Folic acid and reduced folate ((6S)5-MTHF) are currently used in supplementation. The aim of this study was to compare the bioavailability of Quatrefolic®, a novel patented (6S)5-MTHF glucosamine salt, with (6S)5-MTHF calcium salt and folic acid in Sprague Dawley rats.

Methods: Fifty-four to fifty-five-day old male Sprague-Dawley rats were divided in 3 treatment groups, each comprising 6 animals, receiving folic acid, (6S)5-MTHF calcium salt or Quatrefolic® at the dose of 70 µg/kg of (6S)5-MTHF equivalents in a single oral administration. Folates were determined in plasma with a HPLC method employing fluorimetric detection. (6S)5-MTHF level was chosen as a convenient end point to evaluate folate absorption. The main pharmacokinetic parameters were calculated (Cmax, tmax, AUC).

Results: Quatrefolic® administration produced a plasmatic (6S)5-MTHF concentration peak (Cmax: 879.6±330.3 ng/mL) 1.8 times higher than (6S)5-MTHF Ca salt (486.8±184.1 ng/mL), and 3.1 times higher than folic acid supplementation (281.5±135.7 ng/mL), while tmax values were similar for the three folate forms. Quatrefolic® supplementation showed AUC8h (1123.9 ng/mL ∙ h) 9.7 times higher than folic acid (114.7 ng/mL ∙ h) and 1.12 times higher than (6S)5-MTHF Ca salt (997.6 ng/mL ∙ h).

Conclusions: Quatrefolic® has demonstrated an enhanced oral bioavailability in comparison to other reduced folates and to folic acid in rats.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Calcium / chemistry
  • Chromatography, High Pressure Liquid / methods
  • Dietary Supplements*
  • Fluorometry
  • Folic Acid / administration & dosage
  • Folic Acid / pharmacokinetics*
  • Glucosamine / chemistry
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Salts
  • Tetrahydrofolates / administration & dosage
  • Tetrahydrofolates / pharmacokinetics*


  • Salts
  • Tetrahydrofolates
  • Folic Acid
  • Glucosamine
  • Calcium
  • 5-methyltetrahydrofolate