Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir

The purpose of this study was to characterize the relationship between plas ma protein binding and the pharmacokinetic disposition of saquinavir during a normal and elevated alpha-1-acid glycoprotein condition. The extent of p lasma binding of [C-14]saquinavir to human plasma, human albumin, and human alpha-1-acid glycoprotein was also assessed. Transgenic mice, which overex press plasma alpha-1-acid glycoprotein, and control mice were given a singl e intravenous injection of saquinavir (10 mg/kg) and plasma samples were ha rvested as a function of time. The extent of [C-14] saquinavir (0.5-30 mug/ ml) plasma protein binding in each group of mice was determined by ultrafil tration. Plasma saquinavir concentrations from in vivo administration were determined by high performance liquid chromatography with tandem mass spect rometry. Saquinavir binding in human plasma and control mouse plasma was si milar (approximately 3% unbound). In contrast, the extent of binding was si gnificantly increased in transgenic mice (1.5% unbound). Furthermore, saqui navir was more extensively bound to alpha-1-acid glycoprotein than to album in (2.1 versus 11.5% unbound). The systemic clearance and volume of distrib ution of saquinavir were significantly reduced in transgenic mice compared with control mice. The results of this study show that alpha-1-acid glycopr otein is the predominant plasma protein to which saquinavir binds. In addit ion, elevations in plasma alpha-1-acid glycoprotein considerably alter the pharmacokinetic disposition of saquinavir. This is consistent with the obse rvations that systemic exposure to saquinavir in human immunodeficiency vir us patients is greater than that in healthy volunteers and that alpha-1-aci d glycoprotein levels increase with the degree of HIV infection.