Sugioka Nobuyuki, Sato Kenji, Haraya Kenta, Maeda Yuta, Yasuda Kyohei, Fukushima Keizo, Ito Yukako, Takada Kanji
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
Biopharm Drug Dispos. 2008 Nov;29(8):469-79. doi: 10.1002/bdd.633.
The HIV protease inhibitor, nelfinavir (NFV), has been used widely for HIV infection. The drug exhibits high binding characteristics to serum protein (unbound fraction: 0.01). The effect of experimentally induced diabetes mellitus on the pharmacokinetics of NFV was investigated, focusing on the change of protein-binding due to the glycosylation of albumin in streptozotocin-induced diabetes mellitus rats (diabetic rats). The unbound fraction of NFV in diabetic rats (0.04) was greater than that in the control (0.015). In diabetic rats, although the AUC of NFV was decreased after both intravenous (control: 1.75+/-0.08, diabetic: 1.36+/-0.17 microg h/ml) and intraduodenal (control: 1.69+/-0.25, diabetic: 1.19+/-0.39 microg h/ml) administrations, the unbound AUC was increased significantly (intravenous, control: 0.026+/-0.001, diabetic: 0.054+/-0.007 microg h/ml, intraduodenal, control: 0.025+/-0.004, diabetic: 0.048+/-0.016 microg h/ml). The unbound total clearance (control: 131.3+/-6.0, diabetic: 64.3+/-8.0 l/h/kg) and the unbound steady state distribution volume (control: 274.0+/-18.0, diabetic: 123.0+/-14.0 l/kg) were decreased significantly; therefore, greater pharmacological effects can be expected in diabetes mellitus. The contribution of increasing the unbound fraction to these results was significantly higher. In addition, there were no significant differences in the systemic and hepatic availability, peak time and mean absorption time between the diabetic and control rats, suggesting that diabetes mellitus did not affect the absorption of NFV.
HIV蛋白酶抑制剂奈非那韦（NFV）已被广泛用于治疗HIV感染。该药物对血清蛋白具有高度结合特性（未结合分数：0.01）。研究了实验性诱导的糖尿病对NFV药代动力学的影响，重点关注链脲佐菌素诱导的糖尿病大鼠（糖尿病大鼠）中由于白蛋白糖基化导致的蛋白结合变化。糖尿病大鼠中NFV的未结合分数（0.04）高于对照组（0.015）。在糖尿病大鼠中，尽管静脉注射（对照组：1.75±0.08，糖尿病组：1.36±0.17μg·h/ml）和十二指肠内给药（对照组：1.69±0.25，糖尿病组：1.19±0.39μg·h/ml）后NFV的AUC均降低，但未结合AUC显著增加（静脉注射，对照组：0.026±0.001，糖尿病组：0.054±0.007μg·h/ml；十二指肠内给药，对照组：0.025±0.004，糖尿病组：0.048±0.016μg·h/ml）。未结合的总清除率（对照组：131.3±6.0，糖尿病组：64.3±8.0 l/h/kg）和未结合的稳态分布容积（对照组：274.0±18.0，糖尿病组：123.0±14.0 l/kg）显著降低；因此，预计糖尿病患者会有更大的药理作用。未结合分数增加对这些结果的贡献显著更高。此外，糖尿病大鼠和对照大鼠之间的全身和肝脏可用性、达峰时间和平均吸收时间没有显著差异，表明糖尿病不影响NFV的吸收。
