Effect of streptozotocin-induced diabetes mellitus on the pharmacokinetics of nelfinavir in rats.
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 microg h/ml) and intraduodenal (control: 1.69+/-0.25, diabetic: 1.19+/-0.39 microg h/ml) administrations, the unbound AUC was increased significantly (intravenous, control: 0.026+/-0.001, diabetic: 0.054+/-0.007 microg h/ml, intraduodenal, control: 0.025+/-0.004, diabetic: 0.048+/-0.016 microg 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.
Sugioka
Nobuyuki
N
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. nsugioka@mb.kyoto-phu.ac.jp
Sato
Kenji
K
Haraya
Kenta
K
Maeda
Yuta
Y
Yasuda
Kyohei
K
Fukushima
Keizo
K
Ito
Yukako
Y
Takada
Kanji
K
D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D019888:Nelfinavir / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin
D019380:Anti-HIV Agents; D013311:Streptozocin; D019888:Nelfinavir