Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
Biopharm Drug Dispos. 2009 Dec;30(9):532-41. doi: 10.1002/bdd.689.
The effect of obesity induced by a high-fat diet on the pharmacokinetics (PK) of nelfinavir (NFV) was investigated, focusing on the change of distribution and elimination caused by dyslipidemia and hepatic steatosis.The plasma unbound fraction (f(u)) of NFV in obese rats (0.61+/-0.03%) was significantly lower than in the control (1.10+/-0.09%), caused by increasing the plasma triglyceride-rich lipoprotein level. After intravenous (i.v.) administration of NFV, the marked decrease of the distribution volume and slower total clearance (39.5% and 69.1% of the control, respectively) caused by the lower f(u) were the main reasons for the significantly higher area under the blood concentration versus time curve (AUC) in obese rats (145.3% of the control). The absorption of NFV after intraduodenal (i.d.) administration in obese rats was significantly greater than in the control (AUC; 170.4% of the control). The increased bile in obese rats was the main reason for the increasing absorption of NFV, and the lower expression of intestinal P-glycoprotein was also considered. On the other hand, although higher AUCs in obese rats were shown, unbound AUCs in the obese rats were slightly lower than in the control, namely, the plasma NFV concentration in obese rats to obtain the same pharmacological effect was higher than in the control, suggesting the difficulty of drug monitoring. These results suggest that it is necessary to pay further attention to therapeutic drug monitoring of NFV in patients manifesting metabolic syndrome, such as dyslipidemia and visceral fat accumulation, including hepatic steatosis.
高脂肪饮食诱导的肥胖对奈非那韦（NFV）药代动力学（PK）的影响进行了研究，重点关注了血脂异常和肝脂肪变性引起的分布和消除变化。肥胖大鼠（0.61+/-0.03%）中 NFV 的血浆未结合分数（f(u)）明显低于对照（1.10+/-0.09%），这是由于血浆富含甘油三酯的脂蛋白水平增加所致。静脉注射（i.v.）给予 NFV 后，由于 f(u)较低，分布容积明显减少，总清除率较慢（分别为对照的 39.5%和 69.1%），是肥胖大鼠血药浓度-时间曲线下面积（AUC）显著升高（对照的 145.3%）的主要原因。肥胖大鼠十二指肠内（i.d.）给予 NFV 的吸收明显大于对照（AUC；对照的 170.4%）。肥胖大鼠胆汁增加是 NFV 吸收增加的主要原因，也考虑了肠道 P-糖蛋白表达降低。另一方面，尽管肥胖大鼠的 AUC 较高，但肥胖大鼠的未结合 AUC 略低于对照，即肥胖大鼠获得相同药理效果的血浆 NFV 浓度高于对照，提示药物监测困难。这些结果表明，对于表现出代谢综合征（如血脂异常和内脏脂肪堆积，包括肝脂肪变性）的患者，有必要进一步关注 NFV 的治疗药物监测。
