Resveratrol: Overcoming Poor Bioavailability

Resveratrol is one of the most well-characterized anti diabetic, antiatherogenic and neuroprotective polyphenols.  Although red wine was initially thought to be a significant source, most wines contain less than 15 mg per liter.  Attempts to identify the molecular mechanisms in vitro have utilized very high concentrations (in the micromolar range), and have been met with nearly universal success.  However, in vivo, resveratrol is ephemeral—it is metabolically inactivated so rapidly that several human pharmacokinetic trials have reported plasma concentrations close to zero.  Thus, unless a micromolar range in plasma and target sites can be attained, much in vitro data holds a paucity of external validity.

How can we improve bioavailability?  I will explore in a later post, but today I will suggest that the field open itself to the reasoning of drug development. What woefully befalls resveratrol in the body is metabolic inactivation via glucuronidation at 1 or more aromatic hydroxyl groups.  A medicinal chemist would suggest we “cap” these moieties to increase metabolic stability, as more bulky functional groups offer steric effects to deter UDP glucurosyltransferase.  However, within the domain of dietary supplements, I cannot modify the molecule in a laboratory into something so arcane.  That is the game of drug discovery; an enthralling game—add something here, clip there, fashion a natural product to make it better.  It is a savory and dangerous convergence of creativity and synthetic chemistry.

Nature is often a half-step ahead of our pharmacologic resolve.  Like the most brilliant medicinal chemists, plants are curious, astute and goal-oriented. Their knack for adjusting their own chemical composition is the resounding weapon—the means of their terrestrial survival over the last 450 million years.  Plants, including the grapevine, are masters in the art of versatility, and fruits can generate stilbenes and other phenolics in serial fashion.  In this case, a creative semisynthetic dream may not be dashed.

Enter structure-based polyphenol prospecting, with a leading example– pterostilbene, which is simply resveratrol capped fortuitously by methyl groups where metabolic inactivation occurs.  It is particularly abundant in blueberries.  A recent animal study reveals that pterostilbene has a bioavailability of 80% compared to 20% for resveratrol.

From nature’s exquisite and diverse palate, a structural analog with a set of superior behaviors was selected.  Unfortunately, this method of raw material prospecting has not been utilized to its potential.  Some new ideas will be discussed in forthcoming posts.

Pterostilbene’s methoxy groups resist phase II inactivation, following a very basic pharmacokinetic drug optimization principle.

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