Analytical characterization and comparison of the blood-brain barrier permeability of eight opioid peptides

Opioid drugs, including the newly developed peptides, should penetrate the blood-brain barrier (BBB) for pain management activity. Although BBB transport is fragmentarily described for some mu-opioid peptides, a complete and comparative overview is currently lacking. In this study, the BBB transport of eight opioid peptides (EM-1, EM-2, CTAP, CTOP, DAMGO, dermorphin, TAPP and TAPS) is described and compared. In addition, the metabolic stability in plasma and brain was evaluated. The highest influx rate was obtained for dermorphin (K-in =2.181 mu l/(g x min)), followed by smaller rates for EM-1, EM-2 and TAPP (K-in=1.06-1.14 mu l/(g x min)). Negligible influx was observed for DAMGO, my and TAPS (K-in = 0.18-0.40 mu l/(g x min))and no influx for CTAP. Capillary depletion revealed that all peptides reached brain parenchyma for over 75%. Efflux was shown for TAPP (1.112=2.82 min) and to a lesser extent for EM-1, EM-2 and DAMGO (t(1/2) = 10.66-21.98 min), while no significant efflux was observed for the other peptides. All peptides were stable in mouse plasma and brain, with generally higher stability in brain, except for EM-1 and EM-2 which showed plasma half-life stabilities of a few minutes only. (C) 2010 Elsevier Inc. All rights reserved.