Specific renal delivery of sugar-modified low-molecular-weight peptides

To develop a novel delivery system for peptides involving sugar modificatio n, Arg-vasopressin (AVP) was modified by linking it to a variety of sugars via an octamethylene group and the subsequent tissue uptake by rats was the n monitored after administration by i.v, injection. The glucosyl, mannosyl, and 2-deoxyglucosyl derivatives of AVP exhibited selective renal uptake. T hese derivatives were found to be distributed in the proximal tubules of th e renal cortex. In addition, they exhibited specific binding to the kidney microsomal fraction in vitro (K-d = similar to 60 nM), suggesting that they are taken up by a specific recognition mechanism located in the kidneys. F rom the results of the uptake study of glucosyl derivatives, the following points are clear: 1) renal uptake in vivo becomes saturated with increasing dose, and the K-m from the uptake study is almost the same as the K-d obta ined in the binding assay in vitro and 2) because the renal first-pass upta ke extraction is about 70% at a low dose (10 nmol/kg), there is an effectiv e mechanism for uptake from blood. Furthermore. glucosyl and mannosyl deriv atives of oxytocin, a neutral peptide, unlike AVP that is basic, also have high renal uptake clearances Thus, the renal uptake may not be dependent on derivatives having a cationic nature. We conclude that there is a novel tr ansport mechanism in the kidneys that can be used for the specific renal de livery of glycosylated peptides.