RENAL CATABOLISM OF RECOMBINANT HUMAN SOLUBLE CD4 AFTER INTRAVENOUS ADMINISTRATION TO MALE SPRAGUE-DAWLEY RATS

Recombinant soluble CD4 (sT4; mel, wt. 45,000) has been studied extens ively in Sprague-Dawley rats, and substantial renal processing has bee n indicated, In rats and monkeys, renal filtration and precipitation o f sT4 in the distal nephron caused tubular cast nephropathy. Intraveno us pharmacokinetics in the rat demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate, In an effort to determine qua ntitatively the extent to which kidney and other tissues were responsi ble for sT4 catabolism, sT4 was labeled with trace amounts of dilactit ol-[I-125]tyramine and administered intravenously to Sprague-Dawley ra ts (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of protein degradation. It has been used primarily to demonstrate hep atic catabolism of endogenous proteins, Blood samples were drawn for p harmacokinetic analysis, and selected tissues were removed to assess r adiolabel distribution. Comparison of pharmacokinetic parameters deriv ed from total plasma radiolabel and functional ELISA were not signific antly different, Thus, covalent modification of sT4 with dilactitol-ty ramine did not appreciably change the rate of clearance, From 3 to 24 hr after intravenous administration, 81.5 +/- 0.1% of the total admini stered radioactivity was found in the kidney, Approximately 8-13% of t he administered dose was recovered in the liver, Macroscopic autoradio graphy of the kidney demonstrated accumulation of radiolabel in the co rtex, Light microscopic autoradiography of the kidney following intrav enous administration of directly radioiodinated sT4 confirmed cortical processing, because radiolabel was located primarily in epithelial ce lls of P1 and P2 segments of the proximal tubule after low intravenous doses (0.4-4 mg/kg), At 40 mg/kg, distal tubules and cortical collect ing ducts were labeled as well, Thus, sT4 was filtered by the glomerul us, reabsorbed in the proximal tubule, and degraded in the lysosomal c ompartment.