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Pharmacokinetics of human immunodeficiency virus protease inhibitor, nelfinavir, in poloxamer 407-induced hyperlipidemic model rats.

The effect of hyperlipidemia (HL) on the pharmacokinetics of nelfinavir (NFV), a human immunodeficiency virus protease inhibitor, was investigated, focusing on the change of NFV distribution in plasma using poloxamer 407-induced HL model rats (HL rats). The plasma unbound fraction (f(u)) in HL rats (0.20-0.39%) was significantly lower than the control (0.92-1.47%). Lipoprotein level in HL rats was about 5 times higher and low- and very low-density liproteins ratio were 1.7-4.5 times higher than the control. NFV recovery in the triglyceride-rich lipoprotein such as chylomicron, low- and very low-density liproteins fractions of HL rats were significantly higher. The area under the plasma concentration-time curve (AUC) of NFV after intravenous (i.v.: 5 mg/kg) and intraduodenal (i.d.: 30 mg/kg) administration to HL rats (i.v.: 6.12+/-0.48, i.d.: 24.4+/-2.2 microg x h/ml) were higher than the control (i.v.: 1.62+/-0.21, i.d.: 5.00+/-0.36 microg x h/ml). The steady state volume of distribution (Vd(ss)) in HL rats (0.60+/-0.07 l/kg) was lower than the control (6.25+/-0.55 l/kg). Systemic availability (F) in HL rats (66.6%) was higher than the control (51.4 %). Directly absorbed NFV from the gastrointestinal tract to the lymphatic system in HL rats was about 2 times higher than the control. From the results of this study, it was concluded that the increase of AUC was caused by decreasing f(u) and Vd(ss) due to the increase of the triglyceride-rich lipoprotein level. In addition, it was suggested that the increase of absorbed NFV through the lymphatic system, which did not receive the first-pass effect, was one reason for the increase of F in HL rats.