Vol. 298, Issue 1, 57-61, July 2001

In Vivo Pharmacokinetics of Selective µ-Opioid Peptide Agonists

Hazel H. Szeto, Jerry L. Lovelace, Genevieve Fridland, Yi Soong, Joseph Fasolo, Dunli Wu, Dominic M. Desiderio and Peter W. Schiller

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (H.H.S., Y.S., J.F., D.W.); Charles B. Stout Neuroscience Mass Spectrometry Laboratory (J.L.L., G.F., D.M.D.) and Departments of Neurology and Biochemistry (D.M.D.), The University of Tennessee, Memphis, Tennessee; and Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada (P.W.S.)

Recent evidence suggests that highly selective µ-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 µ-opioid receptor (K_i/K_i^µ > 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°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 µ-selectivity, potency, and long duration of action, make them ideal candidates as opioid analgesics.