Satoh Takashi, Tomikawa Yuki, Takanashi Kaori, Itoh Shinji, Itoh Shungo, Yoshizawa Itsuo
Yakuhan Pharmaceutical Co., Ltd., Kitahiroshima, Hokkaido, Japan.
Biol Pharm Bull. 2004 Nov;27(11):1844-9. doi: 10.1248/bpb.27.1844.
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 microM (approximate therapeutic concentration) and 100 microM (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 microM was manidipine (54.4%). When the concentration was 100 microM, 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 microM. On the 17-glucuronidation, all of the drugs showed less than 50% inhibition at the concentration of 1 microM, but at the concentration of 100 microM, drugs that exhibited 50% or higher inhibition consisted of manidipine (79%), chlormadinone acetate (74%), nisoldipine (66%), nitrendipine (60%) and ketoconazole (55%). Although IC(50) values of these drugs were all lower than the K(m) value (285 microM) for the 3-glucuronidation of E2, they were higher than the K(m) value for the 17-glucuronidation (18.8 microM). 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 (V(max)/K(m)) 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.
为了确定药物对雌二醇（E2）葡萄糖醛酸化的抑制作用，以人肝微粒体（混合）作为酶源，在UDP-葡萄糖醛酸存在的情况下，检测了29种已报道可诱发男性乳房发育的药物。基于E2的3-和17-葡萄糖醛酸化的速率常数（分别为11.2和2.52 pmol/分钟/毫克蛋白质），在药物浓度为1 microM（近似治疗浓度）和100 microM（非临床过量浓度）时测定E2葡萄糖醛酸化的抑制百分比。在1 microM浓度下，唯一对3-葡萄糖醛酸化表现出50%或更高抑制作用的药物是马尼地平（54.4%）。当浓度为100 microM时，马尼地平对3-葡萄糖醛酸化表现出100%的抑制作用，对3-葡萄糖醛酸化表现出50%或更高抑制作用的其他药物有尼卡地平（92%）、尼索地平（90%）、硝苯地平（84%）、多潘立酮（81%）、他克莫司（80%）、尼群地平（77%）和酮康唑（69%）。相反，在100 microM浓度下，依普黄酮使雌二醇3-葡萄糖醛酸苷的形成加速了165%。对于17-葡萄糖醛酸化，所有药物在1 microM浓度下的抑制作用均小于50%，但在100 microM浓度下，表现出50%或更高抑制作用的药物有马尼地平（79%）、醋酸氯地孕酮（74%）、尼索地平（66%）、尼群地平（60%）和酮康唑（55%）。尽管这些药物的IC(50)值均低于E2的3-葡萄糖醛酸化的K(m)值（285 microM），但高于17-葡萄糖醛酸化的K(m)值（18.8 microM）。因此，药物对E2葡萄糖醛酸化的作用对E2分子C-3位羟基的影响应大于对C-17位羟基的影响。另一方面，3-和17-葡萄糖醛酸化的代谢清除率（V(max)/K(m)）分别约为E2的2-羟基化代谢清除率的1/14和1/18。该结果表明，当考虑葡萄糖醛酸化对肝肠循环的贡献时，这种代谢抑制在雌激素池中的作用不容忽视。
