Re-evaluation of the relative potency of synthetic and natural alpha-tocopherol: experimental and clinical observations.

Nutritionists generally consider all-rac-alpha-tocopherol and RRR-alpha-tocopherol equivalent in vitamin E activity but disagree whether equivalency requires a dosage ratio of 1.36:1 or 2:1. In contrast, we hypothesize that all-rac- and RRR-alpha-tocopherols are not equivalent in any dosage ratio. Previous observations that all-rac- and RRR-alpha-tocopherols are distributed and eliminated via saturable and stereospecific pathways imply that their relative bioavailability varies with the saturation of these pathways and therefore varies with dosage. Indeed, previous studies observed that the relative bioavailability of all-rac- and RRR-alpha-tocopherols varies between tissues as well as with dose, time after dosing, and duration of dosing. This non-constant relative bioavailability predicts non-constant relative activity (i.e., non-parallel dose-concentration curves predict non-parallel dose-effect curves). Non-constant relative bioavailability suggests that a fixed dosage ratio of all-rac- and RRR-alpha-tocopherols cannot produce a fixed ratio of effects on all processes in all tissues at all times after all dosages. However, previous studies suggest that all-rac- and RRR-alpha-tocopherols have equivalent effects (parallel dose-effect curves) in vitamin E-deficient animals and non-vitamin E-deficient humans. We re-evaluate the data from these animal studies and find non-parallel dose-effect and concentration-effect curves. We discuss pharmacokinetic and pharmacodynamic reasons why previous studies in non-vitamin E-deficient humans did not find non-parallel dose-effect curves for all-rac- and RRR-alpha-tocopherols. We note that saturable elimination predicts that all-rac- and RRR-alpha-tocopherols might inhibit and/or induce elimination of other compounds (including 30-40% of prescription drugs) eliminated via the same saturable pathways, and stereospecific elimination predicts that all-rac- and RRR-alpha-tocopherol have non-parallel dose-effect curves for these interactions.