In vivo pharmacokinetics of selective mu-opioid peptide agonists

Recent evidence suggests that highly selective mu -opioid agonists may prov ide 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 ([Dmt(1)]DALDA) were found to display high binding affinity and much greater selectivity for th e mu -opioid receptor (K-1(delta)/K-1(mu) > 10,000) compared with H-Tyr-D-A la-Gly-MePhe-Gly-ol (DAMGO). In addition, [Dmt(1)]DALDA was 3000-fold more potent than morphine when administered intrathecally. A potential problem w ith peptide analogs as therapeutic agents is their susceptibility to enzyma tic degradation in vivo and short elimination half-lives. In this study, we compared the stability of DAMGO, DALDA, and [Dmt(1)]DALDA after systemic a dministration in sheep. Peptide concentrations were measured using high per formance liquid chromatography-mass spectrometry. When incubated in sheep b lood at 37 degreesC, DAMGO, DALDA, and [Dmt(1)]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 lim ited to blood volume. Plasma clearance of DAMGO (223 ml/kg/h) was 10-fold f aster than DALDA and [Dmt(1)]DALDA (24 ml/kg/h), and their elimination half -lives were 0.24, 7.5, and 1.8 h, respectively. The half-lives of DALDA and [Dmt(1)]DALDA are even longer than morphine or meperidine in sheep. These favorable pharmacokinetic properties of DALDA and [Dmt(1)]DALDA, together w ith their mu -selectivity, potency, and long duration of action, make them ideal candidates as opioid analgesics.