The mechanism of how thiamine is absorbed has been somewhat controversial. One group of researchers concluded that thiamine is only absorbed by a saturable active transport mechanism in the proximal small intestine; however other researchers have shown that thiamine is also absorbed by a passive process [13
]. Several studies by Thomson demonstrated that a maximum amount between 4.8 and 8.3 mg of thiamine could be absorbed by a single oral dose of thiamine hydrochloride. In these studies, subjects were given a single dose oral thiamine between 1 and 20 mg [9
]. In another study, Morrison, found that very little thiamine was excreted in urine when doses above 2.5 mg were given orally [14
]. This saturable active transport mechanism has been attributed to two carriers, thiamine transporter-1 and thiamine transporter-2.
Using a study design where thiamine was infused directly into the lumen of the small intestine, Hoyumpa demonstrated that thiamine was absorbed by an active process at low concentrations (0.2 to 2.0 μM) and by a passive process at higher concentrations (5.0 to 50.0 μM) [15
]. This was also found in an in vitro study [19
]. Thomson found a linear relationship between urinary excretion and oral dose of thiamine between 10 and 50 mg [20
]. This is further supported by Weber who gave a single dose of oral thiamine to 3 subjects (50, 100, or 200 mg) and found that the subject given the largest oral dose also had the highest plasma thiamine levels [21
]. Although, the design of this study and its small sample size limits any conclusions.
Studies to determine the optimal dosing of thiamine for various conditions have not been performed and dosing recommendations appear to be based on limited data. Thiamine deficiency syndromes are typically initially treated with intravenous thiamine between 100 mg once a day and 500 mg three times a day [22
]. Oral dosing of thiamine up to 100 mg/kg divided three times a day have been reported to be required to treat children with genetic abnormalities of pyruvate dehydrogenase. Children with these abnormalities who were not improved by taking thiamine, may have been treated with an inadequate dosage [24
]. In studies of Alzheimer's disease, subjects were treated with 1000 mg of oral thiamine hydrochloride three times a day for 2 to 12 months without any reports of adverse effects [7
]. In a separate experiment, subjects were titrated up to 8000 mg per day over a 1-year period. The only side effects reported were nausea and indigestion in 2 subjects when they reached 7000 and 7500 mg per day [7
]. There have been several clinical trials of thiamine derivatives for a variety of disorders that used doses between 300 and 900 mg per day in divided doses for periods up to 3 months. No side effects were reported in these studies [2
Alternate forms of oral thiamine (S-acyl thiamine derivatives and lipid-soluble thiamine disulfide derivatives) have been developed because they have a much higher bioavailability than thiamine hydrochloride [12
]. Thiamine hydrochloride has been estimated to have a bioavailability between 3.7% and 5.3% [21
]. However, it is not clear that these thiamine derivatives are needed. First, tissue uptake is highly variable across different tissues and different derivatives [12
]. Second, oral thiamine hydrochloride when given over a 1-week period produce blood levels that approach those obtained by intramuscular and intravenous administration [31
]. Finally, in vitro studies that have compared thiamine to thiamine derivatives have generally found them to have similar effects [33
]. In studies where a thiamine derivative was thought to be superior to thiamine hydrochloride, the difference could be completely explained by differences in bioavailability [39
This study has demonstrated that the absorption mechanism is not saturable up to 1500 mg. Our results are consistent with a combination of passive and active transport. The active transport plays a larger role in thiamine absorption at lower doses compared to higher doses. These results contradict the results found by Thomson but is consistent with the animal studies done by Hoyumpa. The constant difference between plasma and whole blood thiamine levels is consistent with a rapid equilibrium between red blood cells and plasma.
This study was limited in that we did not measure tissue levels of thiamine nor did we measure biological effects of high dose oral thiamine hydrochloride. Additionally, while no side effects were reported, this study was not designed to detect adverse events. Our calculation of the coefficient of variation has additional limitations. It includes error related to the analytic method in addition to error related to biologic variation as well as all of the steps between obtaining the blood and its preparation prior to analysis. A greater understanding of the absorption process could have determined if we studied a larger number of thiamine doses and followed the subjects for a longer period of time.