Vol. 280, Issue 3, 1147-1151, 1997

Dynorphin A (1-8) Analog, E-2078, Is Stable in Human and Rhesus Monkey Blood¹

Jim Yu, Eduardo R. Butelman, James H. Woods, Brian T. Chait and Mary Jeanne Kreek

The Laboratory of the Biology of Addictive Diseases (J.Y., M.J.K.), and the Laboratory of Mass Spectrometry and Gaseous Ion Chemistry (B.T.C.), the Rockefeller University, New York, New York and the Department of Pharmacology (E.R.B., J.H.W.), the University of Michigan, Ann Arbor, Michigan 48109

E-2078 is a dynorphin A (1-8) analog, [N-methyl-Tyr¹, N-methyl-Arg⁷-D-Leu⁸] Dyn A (1-8) ethylamide. Its biochemical stability against enzymatic degradation in vitro in human and rhesus monkey blood, and in vivo in rhesus monkey blood was studied using matrix-assisted laser desorption/ionization mass spectrometry. In vitro studies were carried out in freshly drawn human and rhesus monkey blood, incubated at 37°C for various time periods. In vivo studies were conducted by E-2078 i.v. injection to rhesus monkeys, and blood samples were collected at various time points after the injection. It was found that E-2078 was stable against enzymatic degradation in vitro in freshly drawn human and rhesus monkey blood. Minor biotransformation products from E-2078, such as E (1-4), E (1-5) and E (3-6), were detected in vitro in some human and rhesus monkey blood, but they made up less than 5% of the total starting E-2078 peptide. No biotransformation products were detected in the blood samples from in vivo studies. The apparent half-life of elimination of E-2078 in vivo from the rhesus monkey blood was determined to be 44.0 min.