Transport of recombinant CD4 through the rat blood-brain barrier in vivo.
One class of potential acquired immunodeficiency syndrome therapeutics are derivatives of recombinant CD4 (rCD4). Therefore, the present investigations use in vivo techniques to measure the rate at which [3H]rCD4 is transported through the blood-brain barrier (BBB). In addition, the binding of labeled rCD4 to isolated human and bovine brain capillaries is measured. These studies show that [3H]CD4 is removed rapidly from the bloodstream with a half-time of 12.6 +/- 0.9 min. The volume of distribution (Vd) of the protein in brain increases with time and reaches a Vd that is 11.1 +/- 1.1-fold greater than the brain Vd of plasma marker, native rat serum albumin. In addition, [3H]rCD4 is extracted rapidly by the kidney and the ratio of rCD4 Vd to native rat serum albumin Vd in the rat kidney reaches 99 +/- 5 at 60 min after i.v. injection. rCD4 is shown to undergo transcytosis through the BBB using an internal carotid artery perfusion/capillary depletion method coupled with gel filtration fast protein liquid chromatography. In conclusion, these studies report the unexpected finding that rCD4 is transportable through the BBB. rCD4 is a cationic protein and the mechanism of rCD4 transport through the BBB may be analogous to the absorptive-mediated transcytosis of other polycationic proteins.
Pardridge
W M
WM
Department of Medicine, University of California Los Angeles School of Medicine.
Buciak
J L
JL
Yoshikawa
T
T
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015704:CD4 Antigens / Q000008:administration & dosage*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D015704:CD4 Antigens; D011994:Recombinant Proteins