In vivo pharmacokinetics of selective mu-opioid peptide agonists

• Published in: The Journal of pharmacology and experimental therapeutics 2001-07, Vol.298 (1), p.57-61
• Main Authors: Szeto, H H, Lovelace, J L, Fridland, G, Soong, Y, Fasolo, J, Wu, D, Desiderio, D M, Schiller, P W
• Format: Article
• Language: English
• Subjects: Analgesics - blood; Analgesics - pharmacokinetics; Animals; Enkephalin, Ala-MePhe-Gly- - blood; Enkephalin, Ala-MePhe-Gly- - pharmacokinetics; Female; Oligopeptides - blood; Oligopeptides - pharmacokinetics; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Sheep - metabolism
• ISSN: 0022-3565

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.