Inhibition of 2-methoxyestradiol glucuronidation by probenecid.
2-Methoxyestradiol (2ME2), a metabolite of estradiol, has antitumor activity in vitro.
However, potential clinical applicability has been limited by its low oral
bioavailability. Glucuronidation via UDP-glucuronyl transferases (UGTs) is the major
metabolic pathway that is responsible for the low oral bioavailability of 2ME2. In the
present study, probenecid was evaluated in vitro as ... read morean inhibitor of 2ME2 glucuronidation
for purposes of enhancing 2ME2 bioavailability. Human liver microsomes were used to
determine kinetic parameters for transformation of 2ME2 to its glucuronide metabolites
(M1, M2), and inhibition of the reactions by probenecid. According to the study results,
M1 and M2 formation from 2ME2 proceeded with features of substrate inhibition.
Probenecid inhibited metabolite formation, with inhibition constant (Ki) values of 0.9
and 2.6 mM, respectively. Inhibition was reversible, with mixed
competitive-noncompetitive characteristics. In conclusion, the Ki values for probenecid
inhibition of 2ME2 glucuronide formation, when compared to maximum probenecid plasma
concentrations anticipated clinically, indicate that probenecid coadministration has the
potential to augment systemic plasma levels of 2ME2 in
Thesis (M.S.)--Tufts University, 2015.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: David Greenblatt.
Committee: John Castellot, and Emmanuel Pothos.
Keyword: Pharmacology.read less
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