Perri J, Fong KL, Bugelski J, Kirsch R; International Conference on AIDS.

Int Conf AIDS. 1990 Jun 20-23; 6: 201 (abstract no. S.B.461).

Departments of Drug Delivery, Experimental Pathology & Drug Metabolism, SmithKline and French Laboratories, King of Prussia, Pa. 19406, USA

Soluble CD4 (sT4) has been proposed as a potential candidate in AIDS therapy as it effectively blocks the interaction of HIV with its cell surface receptor on target lymphocytes. However, little is understood about the in vivo behavior of this molecule, particularly in reference to routes and mechanism of sT4 clearance from the circulation. To address this issue, dynamic gamma scintigraphic analysis of the routes and kinetics of clearance was conducted. [123I] - sT4 was administered to male rats (N=4) at 0.4, 4.0 or 40.0 mg/kg by bolus i.v. injection and the radioactivity in liver, spleen, lung, kidney, bladder and heart determined every 10 seconds for 30 minutes by analysis of the scintigraphic images. At 0.4 and 4.0 mg/kg accumulation of radiolabel in both kidneys was observed within 2 minutes with minimal radiolabel in the bladder. Cumulative urinary radioactivity was TCA soluble, suggesting renal metabolism or dehalogenation of the radiolabeled molecule. At 40 mg/kg, rapid accumulation of label was observed in the kidneys and urinary bladder. The urinary material was greater than 60% TCA precipitable, suggesting urinary elimination of intact sT4 at high doses. To further investigate the renal handling of sT4, the distribution of sT4 in the kidney was analyzed by light microscopic autoradiography. At 10 minutes post administration of 0.4 or 4.0 mg/kg [125I] - sT4, grains can only be observed concentrated over epithelial cells in the P1 and P2 segments of the proximal tubule, whereas at 40 mg/kg concentration grain can also be observed in the lumen of both the distal tubule and collecting duct. Collectively, these data suggest that the kidney is a major organ of elimination for sT4 and that there is a saturable uptake pathway for sT4 in the proximal tubule epithelial cells that may explain absence of urinary sT4 at the lower doses.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Animals
• Antigens, CD4
• HIV
• HIV Seropositivity
• Kidney
• Kidney Tubules, Proximal
• Liver
• Male
• Rats
• Recombinant Proteins
• SK&F 106528
• Spleen
• Urinary Bladder
• immunology
• methods

Other ID:

• 30046190

UI: 102196275

From Meeting Abstracts