Pharmacokinetic analysis and cellular distribution of the anti-HIV compound succinylated human serum albumin (Suc-HSA) in vivo and in the isolated perfused rat liver.
After intravenous injection of a low dose (25 micrograms/kg) in rats, the anti HIV-1 compound succinylated human serum albumin (Suc-HSA) is taken up mainly in the liver and spleen and is proteolytically degraded. Ten minutes after injection of 125I-Suc-HSA, 72 and 14% of the dose were found in the liver and spleen, respectively. With immunohistochemistry we demonstrated that in both organs, Suc-HSA was specifically endocytosed in endothelial cells. In the isolated perfused rat liver preparation, liver uptake was shown to be saturable, with a Km of 2.9 10(-8) M and a Vmax of 2.4 micrograms/min/100 g body weight. The apparent Km and Vmax in vivo were 2.2 10(-7) M and 10.3 micrograms/min/100 g, respectively. Uptake in liver and spleen was inhibited by preadministration of an excess of formaldehyde-treated albumin and with polyinosinic acid, indicating the involvement of the scavenger receptor, as anticipated for such polyanionic compounds. Suc-HSA is not absorbed intact from the colon and the ileum. After injecting (i.v.) rats with a high dose of Suc-HSA (10 mg/kg), the elimination t1/2 was 3 hr, and therefore, sustained plasma levels above the concentration needed for in vitro anti-HIV-1 activity can be achieved.
Jansen
R W
RW
Department of Pharmacology and Therapeutics, University Centre for Pharmacy, Groningen State University, The Netherlands.
Olinga
P
P
Harms
G
G
Meijer
D K
DK
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D012709:Serum Albumin / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism; D013386:Succinates / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D012709:Serum Albumin; D013386:Succinates; C034877:succinylalbumin