Renal drug targeting using a vector "alkylglycoside".
A specific sugar-modified peptide has previously been shown to have renal targeting potential in vivo and to have a specific binding site which has been identified in the kidney membrane fraction. In this report, we studied the inhibitory effects of glycosylated derivatives on the binding of [3H]Glc-O-C8-AVP [a glucosylated derivative of Arg8-vasopressin (AVP), Kd = 55 nM] to clarify the structural requirements necessary for renal recognition. Glc-S-C7-Me (octyl beta-D-thioglucoside) markedly inhibited the binding, to a much greater extent than Glc-O-C7-Me (octyl beta-D-glucoside) and Gal-S-C7-Me (octyl beta-D-thiogalactoside). Also, [3H]Glc-S-C7-Me was shown to have a specific binding site on the kidney membrane (Kd = 17 nM, Bmax = 24 pmol/mg protein) rather than the liver membrane and, in addition, Glc-S-C7-Me exhibited effective and selective renal uptake in vivo. To examine the possibility that Glc-S-C7-Me might be of practical use as a renal targeting vector, AVP, tryptamine and 4-nitrobenz-2-oxa-1,3-diazole were modified with Glc-S-C8- and the tissue uptake of the resulting derivatives was evaluated. All of these derivatives showed clear renal targeting potential because the apparent uptake clearance by the kidney was greater than 3 ml/min/g kidney in each case. As far as the AVP derivatives were concerned, derivatives having different numbers of methylene groups were compared with Glc-S-C8-AVP. Glc-S-C11-AVP exhibited increased kidney targeting potential, whereas that of Glc-S-C5-AVP was reduced. These differences suggest that the "alkylglycoside" moiety is important for renal uptake. In addition, these renally targeted derivatives inhibited the binding of [3H]Glc-S-C7-Me to the kidney membrane fraction. Our findings allow us to conclude that the alkylglycoside is a suitable candidate vector for renal targeting.
Suzuki
K
K
Drug Delivery System Institute, Ltd., Noda-shi, Chiba, Japan.
Susaki
H
H
Okuno
S
S
Sugiyama
Y
Y
D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives; D000478:Alkylation; D000818:Animals; D001127:Arginine Vasopressin / Q000737:chemistry; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D016503:Drug Delivery Systems; D006031:Glycosylation; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013863:Thioglucosides / Q000008:administration & dosage*; D014363:Tryptamines / Q000378:metabolism
D010455:Peptides; D013863:Thioglucosides; D014363:Tryptamines; D001127:Arginine Vasopressin; C030820:tryptamine; C042989:n-octyl-beta-D-thioglucopyranoside; D009327:4-Chloro-7-nitrobenzofurazan