Novel drug delivery system to bone using acidic oligopeptide: Pharmacokinetic characteristics and pharmacological potential

Citation
T. Sekido et al., Novel drug delivery system to bone using acidic oligopeptide: Pharmacokinetic characteristics and pharmacological potential, J DRUG TAR, 9(2), 2001, pp. 111-121
Citations number
16
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF DRUG TARGETING
ISSN journal
1061-186X → ACNP
Volume
9
Issue
2
Year of publication
2001
Pages
111 - 121
Database
ISI
SICI code
1061-186X(2001)9:2<111:NDDSTB>2.0.ZU;2-4
Abstract
We synthesized fifteen oligopeptides consisting of Asp or Glu conjugated wi th a fluorescent probe, 9- fluorenylinethylchloroformate (Fmoc). In the in vitro binding assay to putative hydroxyapatite (HA), the affinities of thes e conjugates depended only on the number of amino acid residues, not on the ir optical characters (L or D) or their species (Asp or Glu). In an in vivo experiment involving a single i.v. injection of Fmoc-D-Asp oligopeptides i nto mice, peptides consisting of over six Asp residues were selectively dis tributed to the bone. Then, we synthesized estradiol-17 beta -succinate-(L- Asp)(6) [E-2-(L-Asp)(6)] and studied its pharmacokinetic characteristics an d its antiosteoporotic effects on ovariectomized (OVX) mice. Although the d istribution volume of E-2-(L-Asp)(6) was significantly smaller than that of E-2, E-2-(L-Asp)(6) was selectively distributed in the bone after i.v. inj ection and gradually decreased during 7 days. E-2-(L-Asp)(6) effectively pr evented OVX-induced bone loss, without altering the uterine weight, in the dosage range of 0.11 to 1.1 mu mol/kg once a week, while E-2 increased both the bone mineral density and uterine weight at 0.37 mu mol/kg every third day. The results suggest that acidic oligopeptide may be useful for drug de livery to bone and E-2-(L-Asp)(6) is a good candidate as an anti-osteoporos is drug without the adverse side effects of E-2.