Benfotiamine, a Synthetic S-acyl Thiamine Derivative, has Different Mechanisms of Action and a Different Pharmacological Profile Than Lipid-soluble Thiamine Disulfide Derivatives

Marie-Laure Volvert; Sandrine Seyen; Marie Piette; Brigitte Evrard; Marjorie Gangolf; Jean-Christophe Plumier; Lucien Bettendorff


BMC Pharmacol 

In This Article


Mechanism of Action of Benfotiamine

In 1961, Wada et al. reported the physicochemical properties of benfotiamine and its possible use as a therapeutic agent.[31] Benfotiamine is more easily absorbed by the body and oral administration results in higher thiamine and ThDP blood levels in animals than an equivalent dose of thiamine. A few years, later Shindo and coworkers[32,33,34,35] studied in more detail the mechanism of absorption and the metabolic fate of benfotiamine in animal tissues. Their results suggested that benfotiamine (given orally) is first dephosphorylated to S-benzoylthiamine by the ecto-alkaline phosphatase present in the brush borders of intestinal mucosal cells. The more lipophilic S-benzoylthiamine then diffuses through the membranes of intestinal and endothelial cells and appears in the venous mesenteric blood. A significant part of S-benzoylthiamine is captured by erythrocytes[34] and converted to free thiamine through a slow non-enzymatic transfer of the S-benzoyl group to SH groups of glutathione. In the liver, the remainder can be enzymatically hydrolyzed to thiamine and benzoic acid by thioesterases present in the hepatocytes. On the other hand, thiamine disulfide derivatives require a reduction either enzymatically in the liver by glutathione or non enzymatically in blood by glutathione and possibly other substrates.[36] In the present work, we show that after oral administration of benfotiamine to mice, free thiamine appears in the liver at a fast rate, reaching a maximum after one hour, while in the blood the maximum is reached only after two hours (Fig. 3). We therefore propose that most of the S-benzoylthiamine present in the mesenteric blood is captured by the liver and transformed into thiamine. The excess thiamine formed is then rapidly released into the blood stream, as shown by the fast decrease of thiamine content in the liver after 1-2 hours (Fig. 3). Such a scheme is in agreement with an earlier report that, after infusion of benfotiamine to the small intestine of the dog, mainly free thiamine (not S-benzoylthiamine) was detected in the carotid blood.[35] Free thiamine is not lipophilic and cannot cross the blood-brain barrier by simple diffusion. Transport of blood thiamine to the brain parenchyma is carrier-mediated and it is a slow process.[37] In the present study, we find that blood thiamine concentration in the control animals is approximately 0.4 µmol/l, a value close to the half-maximal activation constant for the high affinity transport of thiamine across the blood-brain barrier.[8] Though a second, low affinity, component of thiamine transport was also observed, its contribution was small. Thus, raising free blood thiamine concentrations does not necessarily lead to an important increase in thiamine transport across the blood-brain barrier. It is therefore not very surprising that benfotiamine administration does not lead to an increase in total thiamine content of the brain (Figs 2, 3 and 4). It should be noted however that one study showed a 90% increase of ThDP levels in the brains of rats that received a dose of 1645 mg of benfotiamine/kg of diet for 6 months.[27]

Differences Between Benfotiamine and Lipophilic Thiamine Disulfide Derivatives

Wada et al. already noted that benfotiamine was sparingly soluble in organic solvents such as benzene, chloroform and methanol, but was readily soluble in aqueous media at pH≥8.0.[31] This is not surprising as the phosphoryl group of benfotiamine has two negative charges at alkaline pH. Here, we confirm that benfotiamine is sparingly soluble in water at pH≤7.0 and cannot be dissolved in octanol or oils. Thus benfotiamine should not be classified as a "lipophilic" compound as many authors still do.[10,24,25,38] Indeed, benfotiamine appears unable to diffuse across cell membranes. We have shown here that intracellular thiamine content is not increased in cultured neuroblastoma incubated in the presence of 10 µM benfotiamine, while it was increased ten-fold after incubation with 10 µM sulbutiamine.[29] Moreover, after a chronic treatment of rats with sulbutiamine intracellular thiamine derivatives were increased by respectively 250% (thiamine), 40% (ThMP), 25% (ThDP) and 40% (ThTP).[14]

This is in apparent contradiction with results obtained with cultured cells of endothelial origin,[18,19,20,39] showing that benfotiamine is able to counteract glucose toxicity in these cells by increasing transketolase activity. However, the benfotiamine concentrations used were 50-100µM, much higher than in our study. Hammes et al. even report that there was no effect on transketolase activity in cultured endothelial cells at 10 or 25µM.[18] In any event, this is no proof that benfotiamine is able to cross the membranes: indeed, cultured endothelial cells seem to possess an ecto-alkaline phosphatase.[40] It is therefore likely that, in these cells, the added benfotiamine is at least partially dephosphorylated to S-benzoylthiamine that can enter the cells as in the case of the intestinal mucosa. The slow dephosphorylation to S-benzoylthiamine might also explain the lag period observed between the addition of benfotiamine to thiamine-depleted Neuro 2a cells and the increase in intracellular thiamine derivatives (Fig. 6). In erythrocytes, it was shown that fursultiamine, a lipophilic disulfide, is rapidly incorporated into the cells while benfotiamine is not.[41] Taken together, these results strongly suggest that benfotiamine is unable to cross plasma membranes unless it is dephosphorylated.

Benfotiamine and Sulbutiamine Have Different Pharmacological Profiles

Since the discovery of allithiamine,[9] a number of derivatives were synthesized. These showed higher bioavailability than thiamine hydrochloride or mononitrate. Lipid-soluble thiamine derivatives were developed mainly in Japan for the treatment of beriberi. It was therefore surprising that sulbutiamine appeared to exert specific effects on brain function. Indeed, it seems to improve memory in rodents[42,43] and, in humans, it seems to be beneficial against functional asthenias.[13,44,45] These effects have not been reported with thiamine. This difference might be explained if we assume that sulbutiamine (or its degradation product thiamine disulfide) can cross the blood-brain barrier and have specific actions in neurons. However, there is so far no direct evidence that untransformed sulbutiamine is indeed found in the brain. Concerning benfotiamine, there is no evidence that it has any specific effect on the central nervous system, but during the last few years, there was considerable interest in the therapeutic potential of benfotiamine in peripheral tissues. Indeed, it was found effective for the protection of diabetic complications such as diabetic neuropathy[18,19,20,21,22,23] and alcoholic neuropathy.[46] Our results are in agreement with the different pharmacological profiles of sulbutiamine and benfotiamine. We previously found that sulbutiamine treatment significantly increases thiamine, ThMP, ThDP and ThTP content of rat brain,[14] while the present results show that benfotiamine, at a twice higher dose, is unable to raise the levels of intracerebral thiamine phosphate derivatives (Figs 2, 3 and 4). This is in agreement with a previous study showing that after administration of 3H-benfotiamine, liver and kidney were labeled to a higher degree than brain and muscles,[47] but this study did not make a difference between benfotiamine and its labeled metabolites and degradation products. Furthermore our results on cultured neuroblastoma cells show that benfotiamine, in contrast to sulbutiamine, does not easily cross cell membranes (Figs 5 and 6). It would therefore be interesting to test whether a thiamine disulfide compound such as sulbutiamine or fursultiamine, would not be more efficient and act at lower concentrations than benfotiamine in counteracting diabetic complications. A recent study has shown that, at high concentration (300µM), benfotiamine exerts a direct antioxidant effects in three different kidney cell lines, independently of its transformation in thiamine and increased transketolase activity.[48] It is however not yet clear to what extent, if any, this may be involved in the improvement of diabetic complications.


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