Effect of streptozotocin-induced diabetes mellitus on the pharmacokinetics of nelfinavir in rats
Corresponding Author
Nobuyuki Sugioka
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, JapanSearch for more papers by this authorKenji Sato
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKenta Haraya
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorYuta Maeda
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKyohei Yasuda
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKeizo Fukushima
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorYukako Ito
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKanji Takada
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorCorresponding Author
Nobuyuki Sugioka
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, JapanSearch for more papers by this authorKenji Sato
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKenta Haraya
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorYuta Maeda
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKyohei Yasuda
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKeizo Fukushima
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorYukako Ito
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorKanji Takada
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
Search for more papers by this authorAbstract
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 µg h/ml) and intraduodenal (control: 1.69±0.25, diabetic: 1.19±0.39 µg h/ml) administrations, the unbound AUC was increased significantly (intravenous, control: 0.026±0.001, diabetic: 0.054±0.007 µg h/ml, intraduodenal, control: 0.025±0.004, diabetic: 0.048±0.016 µg 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. Copyright © 2008 John Wiley & Sons, Ltd.
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