title: In vivo pharmacokinetics of selective mu-opioid peptide agonists.
abstract: Recent evidence suggests that highly selective mu-opioid agonists may provide good analgesia with less development of tolerance and dependence. H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA) and H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA) were found to display high binding affinity and much greater selectivity for the mu-opioid receptor (K(i)delta/K(i)mu) > 10,000) compared with H-Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO). In addition, [Dmt1]DALDA was 3000-fold more potent than morphine when administered intrathecally. A potential problem with peptide analogs as therapeutic agents is their susceptibility to enzymatic degradation in vivo and short elimination half-lives. In this study, we compared the stability of DAMGO, DALDA, and [Dmt1]DALDA after systemic administration in sheep. Peptide concentrations were measured using high performance liquid chromatography-mass spectrometry. When incubated in sheep blood at 37 degrees C, DAMGO, DALDA, and [Dmt1]DALDA were stable over 2 h. When given intravenously to sheep, the apparent volume of distribution was 50 to 80 ml/kg for all three peptides, suggesting that distribution was limited to blood volume. Plasma clearance of DAMGO (223 ml/kg/h) was 10-fold faster than DALDA and [Dmt1]DALDA (24 ml/kg/h), and their elimination half-lives were 0.24, 1.5, and 1.8 h, respectively. The half-lives of DALDA and [Dmt1]DALDA are even longer than morphine or meperidine in sheep. These favorable pharmacokinetic properties of DALDA and [Dmt1]DALDA, together with their mu-selectivity, potency, and long duration of action, make them ideal candidates as opioid analgesics.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA. hhszeto@cornell.edu
authors.forename: H H
authors.initials: HH
authors.lastname: Szeto
authors.forename: J L
authors.initials: JL
authors.lastname: Lovelace
authors.forename: G
authors.initials: G
authors.lastname: Fridland
authors.forename: Y
authors.initials: Y
authors.lastname: Soong
authors.forename: J
authors.initials: J
authors.lastname: Fasolo
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: D M
authors.initials: DM
authors.lastname: Desiderio
authors.forename: P W
authors.initials: PW
authors.lastname: Schiller
mesh_terms: D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D012756:Sheep / Q000378:metabolism
chemical_list: C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D000700:Analgesics; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide