Binding characteristics of KNI-272 to plasma proteins, a new potent tripeptide HIV protease inhibitor

Biopharmaceutics & Drug Disposition
A KiriyamaK Takada

Abstract

The binding characteristics of KNI-272, a potent and selective human immunodeficiency virus (HIV) protease inhibitor, were evaluated in rat and human plasma, and in solutions of human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA). The unbound fractions (Fu) of KNI-272 were 12.13 and 2.24% in rat and human plasma, respectively, at the drug concentration of 1.0 microgram mL-1. Although KNI-272 binds to both AAG and HSA, the Fu of KNI-272 in AAG solution was 1.83%, and only one-quarter of that in HSA solution (Fu = 6.78%). Binding displacing agents, such as disopyramide, warfarin, diazepam, and digitoxin, were used to determine the binding site of KNI-272 on these plasma proteins. The Fu of KNI-272 in AAG solution increased 14-fold when disopyramide was added to the AAG solution. In addition, warfarin, diazepam, and digitoxin were added to HSA solution as representative drugs bound to distinct binding sites on HSA, namely sites I, II, and III, respectively. The Fu values of KNI-272 in HSA solution significantly increased when warfarin and diazepam were added. In particular, with the addition of warfarin to HSA solution, the Fu of KNI-272 increased to 16%. The modified Scatchard plots of KNI-272 binding to AAG and H...Continue Reading

Citations

Nov 5, 1998·Journal of Controlled Release : Official Journal of the Controlled Release Society·Z HuK Takada
Aug 10, 2001·Drug Metabolism Reviews·Z H Israili, P G Dayton
Sep 20, 2006·British Journal of Clinical Pharmacology·Sreeja SudhakaranRoger L Nation
Aug 10, 1999·Biopharmaceutics & Drug Disposition·A KiriyamaK Takada

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