Inhibition of 2-methoxyestradiol glucuronidation by probenecid.
OBJECTIVE
2-Methoxyestradiol (2ME2), a metabolite of estradiol, has antitumour activity in vitro. However, potential clinical applicability has been limited by low oral bioavailability. Probenecid was evaluated in vitro as an inhibitor of 2ME2 glucuronidation for purposes of enhancing 2ME2 oral bioavailability.


METHODS
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.


RESULTS
M1 and M2 formation from 2ME2 proceeded with features of substrate inhibition. Probenecid inhibited metabolite formation, with mean inhibition constant (Ki ) values of 0.9 and 2.6 mM, respectively. Inhibition was reversible, with mixed competitive-non-competitive characteristics.


CONCLUSIONS
The Ki values for probenecid inhibition of 2ME2 glucuronide formation, when compared to maximum probenecid plasma concentrations anticipated clinically, indicate that probenecid co-administration has the potential to augment systemic plasma levels of 2ME2 after oral dosage in humans.
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, MA, USA.
Yuli
Y
Qian
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, MA, USA.
Ahmad
A
Sherbini
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, MA, USA.
Bahar
B
Matin
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
Yanli
Y
Zhao
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, MA, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
John
J
Castellot
Graduate Program in Pharmacology and Drug Development, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, MA, USA.|Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
David J
DJ
Greenblatt
D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020719:Glucuronides; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D020719:Glucuronides; D004958:Estradiol; D000077584:2-Methoxyestradiol; D011339:Probenecid
2-methoxyestradiol; bioavailability; glucuronide conjugation; in-vitro metabolism; probenecid