Pharmacokinetics and anti-HIV-1 efficacy of negatively charged human serum albumins in mice

Negatively charged albumins (NCAs, with the prototypes succinylated human serum albumin (Suc-HSA) and aconitylated human serum albumin (Aco-HSA)), modified proteins with a potent anti-human immunodeficiency virus type 1 (anti-HIV-1) activity in vitro, were studied for their pharmacokinetic behaviour in mice and their in vivo anti-HIV-1 efficacy in an HIV-1 infection model in mice. In contrast to the saturation kinetics found in rats, intravenous injections of 10–300 mg/kg for both NCAs showed a linear correlation between the area under the curve (AUC) and the dose. The elimination t 1/2 was 25 and 30 min for Suc-HSA and Aco-HSA, respectively. Preinjections of an excess of formaldehyde-treated albumin (Form-HSA) resulted in plasma levels that were 3- and 4-fold higher for Aco-HSA and Suc-HSA, respectively. These data indicate that elimination is at least partly (scavenger) receptor-mediated. Organ distribution studies 10 min after injection showed an accumulation in liver (Suc-HSA 17.3±6.6% of the dose; Aco-HSA 20.9±2.3%) and lungs (Suc-HSA 12.7±10.5%; Aco-HSA 16.0±13.6). Intraperitoneal injection of 300 mg/kg Suc-HSA resulted in a final bioavailability of about 0.45. Suc-HSA was also evaluated for its in vivo neutralizing capacity in a human-to-mouse chimeric model for HIV-1 infection. Intraperitoneal injections of 300 and 3 mg/kg Suc-HSA, given 15–30 min before the mice were challenged with the virus, sufficed to protect these mice against infection with the HIV-1 III B strain.