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

Abstract and Background


Background: Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration.
Results: Benfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200mM hydroxypropyl-ß-cyclodextrin and the mice received a single oral administration of 100mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 µM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed.
Conclusion: Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.


It is well known that thiamine deficiency results in neurological disorders such as beriberi or Wernicke-Korsakoff syndrome.[1] It is generally assumed that the symptoms arise from decreased activity of thiamine diphosphate (ThDP)-dependent enzymes such as transketolase and pyruvate and oxoglutarate dehydrogenases, with subsequent impairment of carbohydrate metabolism in the brain. It is not known to what extent, if any, the decrease in other thiamine derivatives such as thiamine triphosphate (ThTP,[2]) and the newly discovered adenosine thiamine triphosphate (AThTP,[3]) are involved in the appearance of these symptoms.

In a number of diseases, beneficial effects of the administration of free, unphosphorylated thiamine have been reported. Thus, high-dose thiamine therapy reversed the symptoms of Wernicke's encephalopathy[1] and prevented incipient diabetic nephropathy[4] and diabetic dyslipidaemia[5] in experimental diabetes in the rat. Other reports suggested that thiamine may protect against free-radical mediated neurotoxicity[6] and that it may have a cytoprotective effect on cultured neonatal rat cardiomyocytes under hypoxic insult.[7] These protective effects may be due to increased tissue ThDP levels after thiamine treatment, but effects mediated by other phosphorylated thiamine derivatives such as ThTP and AThTP cannot be ruled out.

It is known that free thiamine is transported across plasma membranes by high affinity carriers,[8] but the rate of transport is generally slow. For that reason, a variety of lipophilic thiamine derivatives have been synthesized. These compounds can easily diffuse through plasma membranes thus bypassing the rate-limiting transport system required for free thiamine. Once incorporated into the cells, these lipophilic derivatives can be rapidly converted to thiamine through enzymatic or non-enzymatic processes. The first lipophilic thiamine derivative was isolated from garlic (Allium sativum) extracts in the early 1950s.[9] It is an allyl disulfide derivative called allithiamine (Fig. 1). Since then, several analogs of this molecule were synthesized with the hope that they would be better absorbed and have a higher bioavailability than thiamine hydrochloride or mononitrate.[10,11] These lipophilic disulfides are often referred to as "allithiamines", in our opinion an improper denomination as they are synthetic molecules not present in Allium species and do not possess any allyl group.

Figure 1.

Structures of the S-acyl derivative benfotiamine and the disulfide compounds allithiamine, fursultiamine and sulbutiamine. The thioester bond in benfotiamine is indicated in blue, while the disulfide bond in allithiamine, fursultiamine and sulbutiamine is drawn in red. The allyl group in allithiamine is indicated in green.

Presently, two lipophilic disulfide derivatives are used as therapeutic agents: thiamine tetrahydrofurfuryl disulfide ("fursultiamine", Fig. 1)[12] and O-isobutyrylthiamine disulfide ("sulbutiamine", Fig. 1).[13] Sulbutiamine turned out to be a psychotropic drug prescribed for the symptomatic treatment of functional asthenias.[13] It was found that chronic treatment with sulbutiamine (52 mg/kg, i.p.) increases thiamine, ThMP, ThDP and ThTP levels in the rat brain as well as in peripheral tissues.[14] Concerning fursultiamine, it is not clear whether it has specific effects on brain function[12] but it exerts a positive inotropic effect in heart muscle.[15,16,17]

S-benzoylthiamine O-monophosphate ("benfotiamine", Fig. 1) is a third derivative with better bioavailability than thiamine. In contrast to the above-mentioned derivatives it is not a disulfide but an S-acyl derivative. It prevents the development and the progression of diabetic complications.[18,19,20,21,22,23] It was suggested that treatment with benfotiamine blocks three major pathways (the hexosamine pathway, the advanced glycation end product formation pathway and the diacylglycerol-protein kinase pathway) of hyperglycemic damage, probably by removal of glyceraldehyde 3-phosphate and fructose 6-phosphate through activation of the pentose phosphate enzyme transketolase.[18] Other beneficial effects of benfotiamine were the reduction of glucose toxicity,[19,20] alleviation of diabetes-induced cerebral oxidative damage,[21] acceleration of the healing of ischemic diabetic limbs in mice[22] and rescue of cardiomyocyte contractile dysfunction in experimental diabetes mellitus.[23]

Whilst different studies show that administration of benfotiamine leads to higher thiamine blood levels than administration of water-soluble thiamine,[10,24,25,26,27] practically no information is available concerning its effects on the brain. The aim of the present study was to check whether oral administration of benfotiamine increases the levels of thiamine and its phosphorylated derivatives in the brain of mice.


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