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Comparative bioavailability of various thiamine derivatives after oral administration

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Abstract

In a multiple change-over study the bioequivalence of 3 thiamine preparations, used therapeutically as neurotropic agents for the treatment of polyneuropathies, was tested in a collective of 7 volunteers. After ingestion of a single dose of either 100 mg benfotiamin CS-benzoylthiamine-o-monophosphate), fursultiamin (thiamintetrahydrofurfuryldisulfide) or thiaminedisulfide, thiamine blood levels were analyzed for a 10-hour period. Thiamine was measured by HPLC after precolumn derivatization to thiochrome. The maximal thiamine concentration Cmax and its time (tmax) in plasma and hemolysate, the area under concentration time curve (AUC), and thiamine excretion in 24-hour urine were assessed as criteria of bioavailability. Additionally the erythrocytic transketolase activity (ETK) and alphaETK were determined as indicators of the cellular thiamine availability. After benfotiamin ingestion a more rapid and earlier increase of thiamine in plasma and hemolysate was observed in contrast to fursultiamin and the disulfide. All biokinetic data demonstrated a significantly improved thiamine bioavailability from benfotiamin compared with the other preparations. The lowest bioavailability was detected with thiamindisulfide. From our results it can be concluded that oral administration of benfotiamin is best suitable for therapeutical purposes owing to its excellent absorption characteristics.
... Benfotiamine (S-benzoylthiamine O-monophosphate, Figure 1B) is one of the lipid-soluble derivatives having much higher bioavailability than the water-soluble form. [9][10][11][12][13] It contains an open thiazole ring, which allows it to pass through the cell membrane, and the open ring is closed by undergoing a reduction reaction making biologically active thiamine. 14 Multifaceted beneficial effects of benfotiamine have been reported such as the reduction of glucose toxicity, 15,16 alleviation of diabetes-induced cerebral oxidative damage, 17 acceleration of the healing of ischemic diabetic limbs in mice, 18 and rescue of cardiomyocyte contractile dysfunction in experimental diabetes mellitus. ...
... 19 Many studies show that administration of benfotiamine leads to higher thiamine blood concentrations than administration of water-soluble thiamine. [9][10][11]20,21 It was revealed that high TDP concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfotiamine. 22 In recent years, most of studies about benfotiamine were focused on pharmacological utilities, while its clinical pharmacokinetic data were inadequate. ...
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Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride.
... 7 S-benzoythiamine can be promptly transformed to water-soluble thiamine (TM) and further transformed to several phosphorylated metabolites, such as thiamine monophosphate (TMP) and thiamine diphosphate (TDP). 8,9 A growing body of evidence has demonstrated that benfotiamine appears to have a therapeutic role in type 2 diabetes and diabetic complications, including neuropathies and nephropathies. 6,8,10,11 Other reports suggest that benfotiamine can reverse cardiomyocyte contractile dysfunction and reduce the neuropathic pain. ...
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Purpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials. Methods: Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10. Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC. Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.
... The bioavailability of orally administered benfotiamine is higher than both thiamine hydrochloride 71 and other thiamine formulations commonly used in clinical settings (thiamine disulfide and fursultiamin). 72 However, benfotiamine is not currently used in fortification. ...
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Thiamine (vitamin B1) is an essential micronutrient in energy metabolism and cognitive and neurological health. Thiamine deficiency disorders (TDDs) have a range of clinical presentations that result in various morbidities and can be fatal if not promptly recognized and treated, especially in infants. To intervene, thiamine intakes by breastfeeding mothers and others at risk of thiamine deficiency should be increased to ensure adequate thiamine intake. Although thiamine fortification programs have a long history in high‐income countries, there are few mandatory fortification programs to address TDDs in low‐ and middle‐income countries (LMICs), particularly in the regions of greatest concern, South and Southeast Asia. This review highlights essential aspects for consideration in the development of a mandatory fortification program in LMICs, including an overview of the data required to model fortification dosing schemes, available thiamine fortificants, and potential fortification vehicles, as well as identifies current knowledge gaps. There are few mandatory fortification programs to address thiamine deficiency disorders in low‐ and middle‐income countries (LMICs), particularly in the regions of greatest concern, South and Southeast Asia. This review highlights essential aspects for consideration in the development of a mandatory fortification program in LMICs, including an overview of the data required to model fortification dosing schemes, available thiamine fortificants, and potential fortification vehicles, as well as identifies current knowledge gaps.
... A benfotiamin a tiamin lipidoldékony változata, biológiai hasznosulása jobb, mint a tiaminé. 71,72,73 A benfotiamin adagolása experimentális diabetesben hatékonynak bizonyult a transzketoláz-enzim aktiválásában, illetve a hexózamin út, a késői glikációs végtermékek, a protein-kináz-C és az NFkappa-B aktiválódás gátlásában is. 74,75 A szakmai érdeklődés a benfotiaminnal kapcsolatban megsokszorozódott azt követően, hogy Brownlee a diabetes idült szövődményeinek megelőzésében a benfotiaminnak centrális szerepet tulajdonított. ...
... Benfotiamine (BF) is a synthetic provitamin and a lipid-soluble analog of thiamine similar to a class of natural products called the allithiamines (Anonymous, 2006, Lonsdale, 2004. The lipid solubility of BF significantly increases the bioavailability of thiamine pyrophosphate (TTP) and dramatically increases the activity of thiamine-dependent enzymes even in alcoholics with thiamine deficiency (Bitsch et al., 1991;Greb and Bitsch, 1998;Loew 1996;Schreeb et al., 1997). The preparation is widely available and utilized over the counter in Japan and Europe and licensed to treat sciatica nerve pain in Germany (Anonymous, 2006). ...
Article
Background Neuropathy as a common complication of hyperglycemia in diabetic patients is probably caused by metabolic and structural changes in extracellular matrix (ECM) of peripheral nerves. This study was designed to evaluate the effects of benfotiamine (BT) on the structural, biological and mechanical characteristics of rat sciatic nerve in hyperglycemic condition.Materials and methodsForty eight adult male Wistar rats were assigned to 6 groups (n = 8): control (healthy rats with no treatment; C), positive control (healthy rats received BT treatment; B), negative control groups 1&2 (hyperglycemic rats kept for 4 and/or 8 weeks; 4WD and 8WD, respectively) and experimental groups 1&2 (hyperglycemic rats treated by daily oral gavage of 100 mg kg− 1 body weight BT for 4 and/or 8 weeks; 4WD + BT and 8WD + BT, respectively). Hyperglycemia was induced by a single intraperitoneal injection of of streptozotocin (55 mg kg− 1 body weight). After a period of experimental period (4 and/or 8 weeks) rats were sacrificed and from each two segments (1 cm length) of left sciatic nerve were sampled. These samples were prepared for histological examinations (light and electron microscopy), collagen IV immunohistochemistry and strength tensile test.ResultsIn comparison to control groups, in 4WD and 8WD groups the amount of type IV collagen was increased, the structure of myelin sheath and nerve fibers were extensively altered and the tensile strength was significantly decreased (p < 0.05) while in 4WD + BT and 8WD + BT groups these abnormalities were attenuated.Conclusions It seems that BT treatment may rescue the sciatic nerve from the hyperglycemic-induced ECM structural abnormality. This beneficial advantage of BT is likely exerted through the modification of glucose metabolism pathways.
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Abstract The present study includes the determination of mercury content in blood of diabetic patients(n=84) the results were compared with control groups(n=80) by using cold mercury vapor atomic absorption spectrometer and the method was optimized for several factors such as the concentration , flow rate , temperature , mixture time . The results have should maximum signals when using (25% w/v) SnCl2 solution and N2 flow rate 0.25 min/l and heating the samples to 80 co . Analytical results had been shown that the detection limit was (1.2) ng/ml Hg the linear rang (0-100) ng/ml Hg, whereas the sensitivity is (0.55) ng/ml and the recovery percentage was (R %) (92.5-102.0) % . On the other hand statical results have displayed that the high mercury content in blood of diabetic patient as age increases life-span groups (60-69) years were (18-26) nglml whereas life-span groups (29-39) years were (2-5) nglml . spectroflurometric method was use for determination of thiamine in whole blood diabetic patients. the method shows sensitivity (0.88) ng/ml on the linear range (0-100) ng/ml and detection limit (1.0) ng/ml and the recovery percent (95-100)% ng/ml . Statical results show decrease content thiamine in blood diabetic patient compared with control and it reaches maximium value (12.90-13.07) ng/ml for males and females respectively at life-span ( 60-69) years . Whereas blood content (9.69,10.54) ng/ml for males and females respectively at life-span ( 29-39) years .
Article
Purpose: Fursultiamine and benfotiamine are lipophilic thiamine derivatives used as oral sources of thiamine. Although there are many publications on the pharmacokinetic (PK) properties of thiamine-containing products, no direct comparisons between these agents . We aimed to compare the PK profiles of these lipophilic thiamine derivatives and to compare the extent of the increase in bioavailability to that of naïve thiamine. Methods: Two randomized, single-dose, 2-way crossover, full PK studies were conducted in healthy Korean male subjects (n = 24 per group). Among the test compounds, fursultiamine was compared with benfotiamine (reference A in study A) and thiamine nitrate (reference B in study B). All formulations were multivitamin preparations containing the test or reference formulation as the major thiamine source. In study A, the plasma and hemolysate concentrations of thiamine and its metabolites were measured, while only the plasma thiamine concentration was assayed in study B. Findings: The systemic thiamine exposure of the test compound was slightly greater than that of reference A, based on the geometric mean ratio (%) of the AUClast value for plasma (116.6%) and hemolysate (137.5%). The thiamine diphosphate (TDP) distribution between plasma and hemolysate showed clear differences according to the formulations, in that more TDP was present in the hemolysate when thiamine was given as the test formulation. The AUClast value of plasma thiamine showed a >300% increase when thiamine was given as the test formulation in study B. The summed total exposure to thiamine (thiamine + TDP in both plasma and hemolysate) observed as a point estimate after the administration of fursultiamine was slightly greater than that with benfotiamine; however, the 90% CI was within the conventional bioequivalence range. Implications: These findings support clear benefits of lipophilic thiamine derivatives in the absorption of thiamine in healthy volunteers. Clinical Research Information Service identifiers: KCT0001419 (study A), KCT0001628 (study B).
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Thiamine is known to have an important role in the protection of different types of cells and tissues against the damage produced by many drugs and toxins. The most important problem limiting the clinical applications of this approach is the poor absorption and bioavailability of thiamine from the sites of administration, a problem which can be solved by the use of the lipid soluble pro-drug for thiamine, benfotiamine. Accordingly, this project was designed to evaluate the serum and tissues availability of thiamine in rats after the administration of single oral dose of benfotiamine compared with that produced by the same oral dose of thiamine, in addition to study the effects of enzyme inducers and inhibitors in this respect utilizing HPLC technique. According to the results obtained in this study one can conclude that thiamine availability after administration of benfotiamine was more in serum, liver, kidney while in the brain more time may be required to reach maximum level.
Article
The bioequivalence of thiamin in 2 therapeutically used preparations was tested in 10 healthy young men. Thiamin was orally administered either as lipophilic benfotiamine or as water-soluble thiamin mononitrate. Biokinetic data, measured as area under the curve and maximal concentration in plasma and hemolysate after ingestion, demonstrated a significantly improved bioavailability from the lipophilic derivative despite an ingested dose of only 40% as compared with the water-soluble salt. A superior cellular efficacy of benfotiamine was also concluded from the short-term stimulation of the thiamin-dependent transketolase activity in erythrocytes.
Article
For a two-way cross-over design, which appears to be the most common experimental design in bioavailability studies, 95%-confidence limits for expected bioavailability can be obtained by classical analysis of variance (ANOVA). If symmetry of the confidence interval is desired about zero (differences) or unity (ratios) rather than about the corresponding point estimator, Westlake's modification can be used. Two nonparametric methods and their adaptations to bioavailability ratios are reviewed, one based on Wilcoxon's signed rank test (Tukey), and the other on Pitman's permutation test. The necessary assumptions and the merits of these procedures are discussed. The methods are illustrated by an example of a comparative bioavailability study. A FORTRAN program facilitating the procedures is available from the authors upon request.