Pharmacokinetics of Human Immunodeficiency Virus Protease Inhibitor, Nelfinavir, in Poloxamer 407-Induced Hyperlipidemic Model Rats(Biopharmacy)
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概要
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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 triglyceriderich 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: 5mg/kg) and intraduodenal (i.d.: 30mg/kg) administration to HL rats (i.v.: 6.12±0.48, i.d.: 24.4±2.2μg・h/ml) were higher than the control (i.v.: 1.62±0.21, i.d.: 5.00±0.36μg・h/ml). The steady state volume of distribution (Vd_<ss>) in HL rats (0.60±0.07l/kg) was lower than the control (6.25±0.55l/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.
- 2009-02-01
著者
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SUGIOKA Nobuyuki
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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HARAYA Kenta
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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MAEDA Yuta
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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FUKUSHIMA Keizo
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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TAKADA Kanji
Department of Pharmacokinetics, Kyoto Pharmaceutical University
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Takada Kanji
Dep. Of Pharmacokinetics Kyoto Pharmaceutical Univ.
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Takada K
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Haraya Kenta
Department Of Pharmacokinetics Kyoto Pharmaceutical University
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Maeda Yuta
Department Of Pharmacokinetics Kyoto Pharmaceutical University
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Takada Kanji
Department Of Biopharmaceutics Kyoto Pharmaceutical University:exploratory Development Laboratories
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Sugioka Nobuyuki
Dep. Of Pharmacokinetics Kyoto Pharmaceutical Univ.
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Takada K
Kyoto Pharmaceutical Univ. Kyoto Jpn
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Fukumoto Kyoko
Department Of Pharmacokinetics Kyoto Pharmaceutical University
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Shibata Nobuhito
Dep. Of Pharmacokinetics Kyoto Pharmaceutical Univ.
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Fukushima K
大正製薬(株)開発研究所薬物動態研究室
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