Pharmacokinetics of Succinylated Serum Albumin in Wistar Rats and Cynomolgus Monkeys: Implications for Dosage Regimens in the Therapy of HIV Infection

P.J Swart, M Schutten, C Smit, G. van Amerongen, Johannes H. Proost, A.DME Osterhaus, D.K F Meijer

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Succinylation of serum albumin produces a negatively charged protein with a potent anti-HIV-1/2 and anti-SIVmac activity. The in vitro IC50 values of Suc-HSA against the respective primate lentiviruses are in the low nanomolar concentration range. Succinylated homologous serum albumin was given intravenously at four different doses, ranging from 0.1 to 10 mg/kg to Wistar rats and Cynomolgus monkeys. Plasma samples were assayed for their drug content using iodinated proteins. The pharmacokinetics parameters were calculated by a single compartment model, taking into account a potential saturable elimination process. In rats as well as in monkeys succinylated serum albumin clearly showed dose-dependent kinetics. The rate of Suc-SSA elimination from the bloodstream in macaques could be described by a Vmax of 11.7 ± 0.2 µg/min kg-1 and a K. of 0.40 ± 0.06 µg/mL (5.5 nM). The elimination of Suc-RSA in rats was characterized by a 10-fold higher V. of 112 ± 29 µg/min kg−1 and a much higher K. of 25 ± 9 µg/mL (340 nM). The volume of distribution was about the plasma volume for both species. In rats, no significant differences were found between the kinetic parameters of Suc-RSA, Suc-HSA, or Suc-SSA. Histochemical staining of tissue sections obtained from the liver, spleen, kidneys, and different lymph nodes showed that endothelial cells and macrophages from the liver and spleen are involved in the clearance of the negatively charged albumins. Since replication of HIV mainly takes place in the lymphoid tissue, uptake of succinylated albumin in this system may imply an interesting therapeutic aspect of the negatively charged albumins.
Original languageEnglish
Pages (from-to)165-171
Number of pages7
JournalDrug Delivery
Issue number3
Publication statusPublished - 1996

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