Effects of obesity induced by high‐fat diet on the pharmacokinetics of nelfinavir,a HIV protease inhibitor,in laboratory rats

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. Copyright © 2009 John Wiley & Sons, Ltd.