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- W2066331352 abstract "The membrane permeation in vivo of therapeutic proteins may be enhanced by conjugation of the protein to cationic import peptides, such as the tat protein of the human immune deficiency virus. The organ uptake, expressed as a percent of injected dose (ID) per gram of tissue, is a function of both membrane permeability and the area under the plasma concentration curve (AUC), which is a function of the plasma pharmacokinetics. The purpose of the present studies was to examine the effect of the tat peptide on the plasma AUC of a model exogenous protein, streptavidin, and to examine the extent to which changes in the plasma AUC influence organ uptake (%ID/g) of the protein. The cationic portion of the tat protein is comprised of a lysine/arginine-rich sequence, designated tat48-58. A biotin analogue of this cationic peptide, tat-biotin, was radioiodinated and injected intravenously into rats with or without conjugation to streptavidin. The unconjugated tat-biotin peptide was nearly instantaneously cleared from plasma by all tissues with a very high systemic clearance of 29 +/- 4 mL/min/kg and a high systemic volume of distribution of 4160 m+/- 450 mL/kg. The plasma clearance of the tat-biotin/streptavidin conjugate, 1.37 +/- 0.01 mL/min/kg, was reduced relative to the clearance of unconjugated tat peptide, but was higher than the plasma clearance of the unconjugated streptavidin, 0.058 +/- 0.005 mL/min/kg. Conjugation of cationic import peptides such as tat48-58 to higher molecular weight proteins results in a marked increase in the rate of removal of the protein from the circulation, which is reflected in the reduced plasma AUC. In summary, tat conjugation of a protein has opposing effects on membrane permeation and the plasma AUC. Therefore, the organ %ID/g is not increased in proportion to the increase in membrane permeation caused by tat conjugation of proteins." @default.
- W2066331352 created "2016-06-24" @default.
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- W2066331352 date "2001-10-27" @default.
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- W2066331352 title "Pharmacokinetics and Delivery of Tat and Tat-Protein Conjugates to Tissues in Vivo" @default.
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- W2066331352 doi "https://doi.org/10.1021/bc0155061" @default.
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