INHIBITION OF RESVERATROL GLUCURONIDATION BY PROBENECID: IN VITRO EFFECTS AND CLINICAL RELEVANCE.
is a naturally occurring antioxidant that is found in high density in sources such as
red wine and grapes. Numerous experimental and in vitro studies reveal the therapeutic
potential of resveratrol in many models of human disease, particularly in cancer
chemoprevention. However, net clearance of resveratrol in vivo is very high, mainly due
to glucuronide conjugation by ... read moreUridine diphosphate glucuronsyl transferases (UGT).
Resveratrol undergoes significant conjugation by UGT enzymes, yielding resveratrol
3-O-glucuronide (R3G) and resveratrol 4'-O-glucuronide (R4G), which has less
pharmacological activity than the parent compound. Using human liver microsomes, the in
vitro effects of probenecid on resveratrol glucuronidation was evaluated in the present
study. The results of the study show that probenecid inhibited R3G formation, with
inhibition constant (Ki) value of 3.17 mM, and 47% inhibition at high concentration of
probenecid. The data indicated a mixed competitive-noncompetitive mechanism of
inhibition. The results suggest that co-administration of probenecid with resveratrol
might increase concentrations of resveratrol in plasma. The relevance of the in vitro
findings is to be tested in a randomized, two-way crossover study, which is needed to
validate the potential value of probenecid as an agent to augment exposure of
resveratrol in humans.
Thesis (M.S.)--Tufts University, 2015.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: David Greenblatt.
Committee: Richard Shader, and John Castellot.
Keywords: Pharmacology, and Pharmaceutical sciences.read less