Reply to Dr. Lonsdale's Letter: Benfotiamine and Allithiamine Should Be Differentiated

Editor:
I read with attention Dr. Derrick Lonsdale's letter taking exception to certain statements made in recent advertisements for AOR's pharmaceutical-grade Benfotiamine supplements. While Dr. Lonsdale deserves our respect for his many years of advocacy of the benefits of the allithiamines and of tetrahydrofurfuryl disulfide in particular, we cannot agree with his objections, which range from mere terminological quibbling to statements which are simply scientifically inaccurate.

Dr. Lonsdale's first objection is to the description of benfotiamine as "an allithiamine." Dr. Lonsdale insists that the term "allithiamine" should only ever be used to refer to one specific compound: that first crystallized by Dr. Fujiwara from heated garlic in the middle of the last century. While it is quite correct to note that the term originally referred to this particular thiamine derivative, the term has since come to refer to the entire class of high-bioavailability thiamine derivatives sharing a common set of biochemical features – a class which includes benfotiamine.

This fact can readily be confirmed in the primary scientific literature. Many investigators specifically describe benfotiamine as being "an allithiamine." For instance, in their randomized, double-blind, controlled study demonstrating the effectiveness of benfotiamine on neurological functioning and symptomology in diabetic neuropathy, Stracke et al. describe benfotiamine as "an Allithiamine," which they explicate to be "a lipid-soluble derivative of vitamin B1 with high bioavailability."¹ Loew, in reviewing the pharmacokinetics of various thiamine derivatives, describes benfotiamine as "an allithiamine," and discusses the "lipophilic thiamine analogues, the allithiamines (acetiamine, benfotiamine, or fursultiamine [TTFD])."² Again, in their pharmacokinetic study of tissue distribution of thiamine vs. benfotiamine, Hilbig and Rahmann describe "benfotiamine, CAS 22457-89-2 as a "lipid-soluble allithiamine."³ Ziems and colleagues, in their recent study on the metabolism of benfotiamine, introduce their study with the statement that "Lipid-soluble thiamine derivatives belonging to the allithiamine group were discovered nearly 40 years ago."⁴ Among these agents, they include S-benzoylthiamine-O-monophosphae (BTMP) – i.e., benfotiamine.

From these and other examples readily identified using a simple PubMed database search,^5,6 and which could doubtless be expanded upon with a hand-search of full-text articles, it is clear that the use of the term "allithiamine" has evolved in scientific usage beyond Fujiwara's original, eponymous "allithiamine" compound, to embrace the entire class of these molecules – prominently including benfotiamine.

Dr. Lonsdale also appears uncomfortable with the use of the term "benfotiamine" to denote BTMP, on the basis that it is "obviously a trade name." While we do use "Benfotiamine" as the name for AOR's specific pharmaceutical-quality benfotiamine supplements, and while it is the first such supplement to be made available in North America, "benfotiamine" is certainly not a trade name: as a perusal of the biomedical literature will clearly show, it is simply a common, generic shorthand term for the compound itself, used in many studies involving BTMP.

Finally, Dr. Lonsdale states that unlike other allithiamines, benfotiamine is "subject to the same natural transport mechanisms" as conventional thiamine salts which "makes the absorption of the thiamine moiety into cells limited," and therefore benfotiamine will "release an intact thiamine molecule outside the cell [emphasis in original]" rendering it no more effective than conventional thiamine salts of increasing cell and tissue thiamine. However, he provides no data to document this belief. Fortunately, abundant data exist to refute this misapprehension.

Loew² specifically states that benfotiamine undergoes the very same process of cellular absorption and reduction as other allithiamines: "Benfotiamine, an allithiamine, contains an open thiozole ring that is closed by reduction within the organism producing physiological thiamine…. Allithiamins differ from water-soluble thiamine derivatives both in their physiochemical properties and their structure, specifically their open thiazole ring. They are so-called prodrugs, which are converted to physiologically active thiamine within the organism by closure of the thiazole ring." The metabolism of benfotiamine is discussed in greater detail in a later review,⁷ which describes the entire process of absorption and disposition of benfotiamine in vivo. Benfotiamine is first taken up across the gut mucosa through dose-proportional passive diffusion and then converted not to thiamine (as Dr. Lonsdale guesses), but to its first metabolite, S-benzoylthiamine. This metabolite is then transported to the cell, where it is again taken up across the neuronal membrane by a process of dose-proportional passive diffusion. Only at this point is S-benzoylthiamine finally subject to intracellular reduction to biologically active thiamine.⁷

That benfotiamine is indeed taken up by cells and tissues more avidly than either thiamine itself or other allithiamines is demonstrated not only by the many clinical and experimental studies which clearly show the superiority of benfotiamine to thiamine in correcting diabetic nerve and kidney dysfunction, but also by direct pharmacokinetic studies documenting its higher accumulation and retention within cells and tissues after both oral and intravenous administration (which latter eliminates the confounding factor of absorption in the GI), and its especially selective incorporation into neural tissue. On these points, see studies reviewed by Loew²; see also many subsequently-published original investigations.^3,8-12 In the present context, Greb and Bitsch's study¹² is of special interest, because it compared benfotiamine to TTFD (which Dr. Lonsdale appears to favor) and thiamine disulfide. These investigators found that benfotiamine was more bioavailable and bioactive than the other two supplements, not only in increasing plasma thiamine levels, but also in raising levels within red blood cells and in increasing biological activity as assessed by absolute transketolase activity.

Finally, Dr. Lonsdale states that "The prosthetic group from BTMP has not, to my knowledge, been studied" and that this bears on benfotiamine's ability to assisting in the excretion of heavy metals. In fact, both sides of this issue have been addressed, both in studies evaluating the metabolism of benfotiamine itself and of its first metabolite, S-benzoylthiamine,^4,13 and in a study directly showing that benfotiamine increases excretion of tissue cadmium stores.¹⁴

I trust that this information satisfactorily addresses Dr. Lonsdale's questions. Extensive information on benfotiamine is also available on our website at www.AOR.ca.

Dr. Traj P.S. Nibber, Director
Advanced Orthomolecular Research

References
1. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6.
2. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther. 1996 Feb;34(2):47-50.
3. Hilbig R, Rahmann H. Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice. Arzneimittelforschung. 1998 May;48(5):461-8.
4. Ziems M, Netzel M, Bitsch I. Biokinetic parameters and metabolism of S-benzoylthiamine-O-monophosphate. Biofactors. 2000;11(1-2):109-10.
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6. Price J, Theodoros MT. The supplementation of alcoholic beverages with thiamine – a necessary preventive measure in Queensland? Aust NZ J Psychiatry. 1979 Dec;13(4):315-20.
7. Loew D. Development and Pharmacokinetics of Benfotiamine In Gries FA, Federlin K. Benfotiamin in the Therapy of Polyneuropathy. New York: Georg Thieme Verlag, 1998; 19-27.
8. Karpov LM, Rozanov Ala, Filippova TO. Characteristic features of 35S-benzoylthiamine monophosphate in albino mice. Vopr Med Khim. 1986 Jul-Aug; 32(4):136-9.
9. Geyer J, Netzel M, Bitsch I, Frank T, Bitsch R, Kramer K, Hoppe P. Bioavailability of water- and lipid-soluble thiamin compounds in broiler chickens. Int J Vitam Nutr Res. 2000 Dec;70(6):311-6.
10. Frank T, Bitsch R, Maiwald J, Stein G. High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfotiamine. Eur J Clin Pharmacol. 20 Jun;56(3):251-7.
11. Frank T, Bitsch R, Maiwald J, Stein G. Alteration of thiamine pharmacokinetics by end-stage renal disease (ESRD). Int J Clin Pharmacol Ther. 1999 Sep;37(9):449-55.
12. Greb A, Bitsch R. Comparative bioavailability of various thiamine derivatives after oral administration. Int J Clin Pharmacol Ther. 1998 Apr;36(4):216-21.
13. Shindo H, Okamoto K, Totsu J. Transport of organic compounds through biological membranes. I. Accumulative uptake of S-benzoylthiamine by human erythrocytes. Chem Pharm Bull (Tokyo). 1967 Mar;15(3):295-302.
14. Yamamoto J, Kaneda Y. Excretion of intracorporeal cadmium with S-benzoylthiamin monophosphate. Bull Environ Contam Toxicol. 1995 May;54(5):745-50.