Mechanisms of Lower Maintenance Dose of Tacrolimus in Obese Patients
Mechanisms of Lower Maintenance Dose of Tacrolimus in Obese Patients
复制标题
DOI：
10.2133/dmpk.dmpk-13-rg-110
复制
发表时间：
2014-08-25
影响因子：
2.1
通讯作者：
Miyamoto, Ken-ichi
中科院分区：
文献类型：
--
作者：
Sawamato, Kazuki;Huong, Tran T.;Miyamoto, Ken-ichi
回顾性分析表明，体重指数 (BMI) 偏瘦（= 18.5 和 = 25）的患者中他克莫司的血液浓度是一致的。 BMI≥25的患者他克莫司的平均维持剂量明显低于BMI小于25的患者。正常饮食喂养的瘦型和肥胖型Zucker大鼠均静脉或口服给予他克莫司。两种途径给药后，肥胖大鼠的他克莫司血药浓度显着高于瘦大鼠。矩分析表明他克莫司的 CLtot 和 V-dss 在瘦大鼠和肥胖大鼠之间没有显着差异。与瘦大鼠相比，肥胖大鼠的生物利用度较高。与瘦大鼠相比，肥胖大鼠肝脏中Cyp3a2的蛋白表达显着降低，而肥胖大鼠小肠中P-gp的表达也显着降低。这些结果表明，与正常和瘦患者相比，肥胖患者中他克莫司的稳态谷浓度可以通过相对较低的剂量得到良好维持，这可能是由于生物利用度增加。
A retrospective analysis suggested that blood tacrolimus concentrations were consistent among patients with a body mass index (BMI) that was lean (= 18.5 and = 25). The average maintenance dose of tacrolimus in patients with BMI >= 25 was significantly lower compared with that in patients with a BMI of less than 25. Lean and obese Zucker rats fed a normal diet were given tacrolimus intravenously or orally. The blood concentrations of tacrolimus in obese rats were significantly higher than those in lean rats after administration via both routes. The moment analysis has suggested that CLtot and V-dss of tacrolimus were not significantly different between lean and obese rats. The bioavailability was higher in obese rats, compared with that in lean rats. The protein expression of Cyp3a2 in the liver was significantly decreased in obese rats, compared with lean rats, while P-gp in the small intestine was also significantly decreased in obese rats. These results suggested that the steady-state trough concentration of tacrolimus in obese patients was well maintained by a relatively low dose compared with that in normal and lean patients, presumably due to increased bioavailability.