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Evaluation of vitamin E potency

Vitamins and Fine Chemicals Research and Development F. Hoffmann–La Roche Ltd CH-4070 Basel, Switzerland

Dear Sir:

Vitamin E (-tocopherol) is available as both RRR--tocopheryl acetate (RRR--TA) and all-rac--tocopheryl acetate (all-rac--TA). Differences in biological activity of these preparations are expressed by an officially accepted potency factor, according to which RRR--TA is 1.36 times as potent as all-rac--TA (1). Burton et al (2) suggested deriving the potency factor from the relative availability of RRR- and all-rac--tocopherol and concluded that the ratio should be closer to 2:1. In most of their studies, an equimolar mixture of d₃-RRR--TA and d₆-all-rac--TA was ingested before biokinetics in human plasma and tissue concentrations in patients were monitored. Single and multiple dosing studies with comparatively high loads of -TA were carried out. Relative availability was expressed as the ratio of d₃--tocopherol to d₆--tocopherol. It seems premature to conclude that the ratio is 2:1, however, because of the following 2 unresolved issues.

1) Is relative bioavailability an indicator of biopotency? The weight potency factor of vitamin E is a relative measure of the functional activity of -tocopherol and its homologues and stereoisomers. Potency reflects the functional response of a compound and usually is expressed in terms of the EC₅₀ (concentration or dose of an effector that produces 50% of the maximal possible effect). The weight potency factor for RRR--TA is the ratio of the EC₅₀ of RRR--TA to the EC₅₀ of all-rac--TA and was assessed by the resorption-gestation assay in rats. Assessment of the weight-potency ratio included administering and testing either RRR--TA or all-rac--TA, a design denoted as the 2-independent-experiments approach. Additional assays based on the prevention or cure of muscular dystrophy in rats, chicks, and rabbits and on the prevention of encephalomalacia in chicks provided almost identical values for the factor. I appreciate the difficulties of conducting similar studies in humans.

Availability of the active compound at the target site is a prerequisite for its efficacy, and therefore potency is dependent on availability. Concentrations in tissues and plasma may be easily related to biopotency, provided the relation between concentration and effect can be described linearly. However, a sigmoidal concentration-effect response curve restricts proportionality to a range of intermediate concentrations only. At high doses, absorption or transport usually becomes a limiting factor and as a result availability does not parallel potency. Thus, changes in bioavailability can result in varying efficacy. Such data are not meaningful for the assessment of potency, which is defined as a property of the compound. Moreover, the functional dose response of the individual -tocopherol stereoisomers was found to be synergistic and not additive (3). These synergistic effects are probably difficult to relate to availability. Obviously, several factors may complicate the evaluation of biopotency from data on relative bioavailability and appropriate validation of such an approach is mandatory.

2) Is the method valid for assessing relative availability? Burton et al (2) concluded that bioavailability of all-rac--tocopherol is roughly half that of RRR--tocopherol, at least in the long term. However, the new method provided a range of values for relative availability because the d₃-d₆ ratio changed with time from <1.5 to 2.0.

The classic approach to assessing relative availability is based on 2 separate applications: 1 for the test and 1 for the reference compound (4). Therefore, classic relative availability has to coincide with availability as determined by the competitive dosing approach, thereby demonstrating the validity of the new approach. For RRR--TA and all-rac--TA, both approaches would be expected to provide identical relative availabilities under conditions of first-order (or dose linear) kinetics.

There are, however, several indications in the paper that the tocopherol plasma kinetics were not linear (eg, lack of dose proportionality in the multiple dosing experiments, washout kinetics of unlabeled tocopherol after administration of high doses of labeled tocopherol, and variation of the d₃-d₆ ratio with time after multiple dosing). These findings are not surprising because at high doses nonlinear kinetics would be expected for a system exerting biodiscrimination. Stereoselectivity is usually mediated by proteins displaying binding saturation. For the discrimination of the 8 stereoisomers of -tocopherol, the hepatic tocopherol transfer protein (TTP) is assumed to play a major role in adjusting plasma and tissue tocopherol concentrations (5). I agree with Burton et al (2) that the configuration at the C-2 position of the molecule is the major determinant of biological differences between the -tocopherol stereoisomers. Discrimination between 2S and 2R forms of -tocopherol is assumed to take place because of lower binding affinity of the 2S forms to TTP (6). Thus, presentation of both RRR- and SRR--tocopherol to TTP will result in preferential binding of RRR--tocopherol. Increasing the relative abundance of RRR--tocopherol will lower the probability of SRR--tocopherol binding to TTP, thereby enhancing the probability for SRR--tocopherol discrimination.

The dose administered in the studies by Burton et al (2) would contain 50% d₃-2R--TA, 25% d₆-2R--TA, and 25% d₆-2S--tocopherol, so that 75% of the 2R forms would compete with 25% of the 2S forms (ratio of 3:1) for TTP binding. By contrast, if the 2 compounds were given separately, administration of all-rac--TA would result in 50% of the 2R forms competing with 50% of the 2S forms (ratio of 1:1). Thus, because of the relatively high abundance of the 2R forms when the 2 forms are given simultaneously, the 2R forms would compete more effectively and bioavailability of the 2S forms would be underestimated compared with that in experiments in which the compounds are given independently.

Because binding to TTP is saturable and stereoselective, the competitive dosing approach is not applicable unless tracer doses are used. At high doses the competitive dosing approach will tend to overestimate relative availability. I agree, however, with the authors that new methods have to be developed to reassess the potency factor in humans, perhaps based on an enhanced understanding of vitamin E function. Nevertheless, revision of the currently accepted potency factor has to rely on an appropriate and validated method.

REFERENCES

1. US Pharmacopoeial Convention, Inc. The national formulary. Rockville, MD: US Pharmacopoeial Convention, Inc, 1979.
2. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue -tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998;67:669–84.[Abstract]
3. Weiser H, Vecchi M. Stereoisomers of alpha-tocopheryl acetate. II. Biopotencies of all eight stereoisomers, individually or in mixtures, as determined by rat resorption-gestation tests. Int J Vitam Nutr Res 1982;52:351–70.[Medline]
4. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Decker, Inc, 1982.
5. Traber MG. Regulation of human plasma vitamin E. Adv Pharmacol 1997;38:49–63.
6. Hosomi A, Arita M, Sato Y, et al. Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 1997;409:105–8.[Medline]

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