Abstract
To determine the inhibition effects of drugs on the glucuronidation of estradiol (E2), 29 drugs that have been reported to induce gynecomastia were examined in the presence of UDP-glucuronic acid using human hepatic microsomes (pooled) as the enzyme source. The percentage inhibition of the E2 glucuronidation was determined at drug concentrations of 1 μM (approximate therapeutic concentration) and 100 μM (non-clinical overdose concentration) based on the rate constants for the 3- and 17-glucuronidation of E2 (11.2 and 2.52 pmol/min/mg protein, respectively). The only drug that exhibited 50% or higher inhibition of the 3-glucuronidation at a concentration of 1 μM was manidipine (54.4%). When the concentration was 100 μM, manidipine exhibited 100% inhibition of the 3-glucuronidation, and other drugs that exhibited 50% or higher inhibition of the 3-glucuronidation were nicardipine (92%), nisoldipine (90%), nifedipine (84%), domperidone (81%), tacrolimus (80%), nitrendipine (77%) and ketoconazole (69%). Conversely, ipriflavone accelerated the formation of estradiol 3-glucuronide in the activity of 165% at the concentration of 100 μM. On the 17-glucuronidation, all of the drugs showed less than 50% inhibition at the concentration of 1 μM, but at the concentration of 100 μM, drugs that exhibited 50% or higher inhibition consisted of manidipine (79%), chlormadinone acetate (74%), nisoldipine (66%), nitrendipine (60%) and ketoconazole (55%). Although IC50 values of these drugs were all lower than the Km value (285 μM) for the 3-glucuronidation of E2, they were higher than the Km value for the 17-glucuronidation (18.8 μM). Thus, the effect of the drugs on the E2 glucuronidation should be greater for hydroxy group at the C-3 than that at the C-17 of E2 molecule. On the other hand, metabolic clearances (Vmax/Km) of the 3- and 17-glucuronidation were about 1/14th and 1/18th of that of the 2-hydroxylation of E2, respectively. The result implies that, when the contribution of the glucuronidation to enterohepatic circulation is taken into consideration, the effect of this metabolic inhibition in the estrogen pool cannot be ignored.
