Rational application of fructose-1,6-diphosphate: From the perspective of pharmacokinetics

Abstract

Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, has been reported to protect susceptible organs during hypoxia or ischemia. However, there is paucity of human data on its pharmacokinetics a er being exogenously administered. In the current study, the preliminary pharmacokinetics of FDP given orally to humans was investigated, and no typical peak was observed in the serum drug-time curve. Then, the pharmacokinetic studies were performed following multiple doses of FDP in rats, and the Caco-2 monolayer model was used to study the absorption of FDP in vitro. The results suggested that plasma FDP concentration was signifi cantly increased a er oral multiple doses of 180 mg kg -1 but not 90 mg kg -1 of FDP, and FDP was partly depleted during the absorption, which was supposed to be consumed by the intestinal epithelium cells. Thus, we conclude that a high dose of FDP should be orally administered in order to get an eff ective plasma level.Keywords: fructose-1,6-diphosphate, ischemia, hypoxia, pharmacokineticsFructose-1,6-diphosphate (FDP) is an endogenous intermediate metabolite of glucose. Most of glucose and fructose is converted to FDP when entering a cell. It has been increasingly recognized that FDP can protect ischemic or hypoxic tissue a er acute ischemia, although the mechanisms have not been fully clarifi ed yet.Previous studies suggested that exogenous FDP could augment the anaerobic carbohydrate utilization and improve the cellular energy metabolism in ischemic and hypoperfused tissues. Hypoxia forces ischemic tissue to anaerobic glycolysis for energy, which yields two molecules of ATP per glucose in contrast to 36 molecules of ATP generated during oxidative phosphorylation (1). Addition of exogenous FDP can produce two more molecules of ATP in an uncompensated anaerobic environment and hence facilitate the recovery of ischemia tissue. FDP breaks down into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, which will further break down into two molecules of pyruvate and fi nally produce two molecules of ATP (Fig. 1).

Fructose-1,6-bisphosphate prevents pulmonary fibrosis by regulating extracellular matrix deposition and inducing phenotype reversal of lung myofibroblasts

“…The level stayed above the base line concentration up to 72h. For rats receiving 180 mg/kg FBP orally every 8 h for 7 consecutive days, FBP levels in plasma peaked at 182 μg/ml after 45 min [36]. To our knowledge, there is no report on the amount of FBP captured by lung after IP administration in mice, although reports can be found that it can prevent ischemic lung injury in rats [37].…”

Comparative study between fructose 1-6 bisphosphate and histidine-tryptophan-ketoglutarate in liver preservation in rats submitted to total cold ischemia

“…During ischemia/reperfusion in control livers, state 4 increased progressively, while FBP suppressed this increase, although it did not affect state 3. Thus, the RCR of livers preserved with FBP was higher compared to control during ischemia/reperfusion 22 . In this study, mitochondrial parameters related to oxidative phosphorylation, show that the inhibition of electron transport through the respiratory chain in state 3, resulting from hypoxia is observed only in 24 hours of cold ischemia and that FBP was able, as well as the HTK, in maintaining values similar to the control in the 6h period, both for O 2 consumption speed in state 3 and the RCR, thus maintaining the ATP synthesis capacity in that period.…”

Fructose 1,6-Bisphosphate as a Protective Agent for Experimental Fat Grafting

“…Vexler et al demonstrated the toxicity of FBP in neonatal rats, which receiving 8,000 mg/kg and 27% of those receiving 6,000 mg/kg of FBP intraperitoneally died, because of the chelation of the ionic calcium, creating a reduction in plasmatic ionic calcium, and resulting in convulsions and cardiac fibrillations. Additionally, according to Li et al study , the consumption of FBP by the intestinal epithelium cells could be a major barrier for FBP absorption during oral administration, and a higher dosage may be used when FBP was given orally to achieve the desired clinical therapeutic effect. In our experiment, the administration of FBP in mice is 4 mg/g intraperitoneally, whereas the recommended dose of FBP for patients is 1 g, tid i.v., that is , 42.8 mg/kg per day.…”