Chemical stabilization of a vasoactive S-nitrosothiol with cyclodextrins without loss of pharmacologic activity

S-Nitrosothiols have been proposed as the endogenous chemical representing the vasoactive endothelium-derived relaxing factor, as well as the active cellular intermediates responsible for the therapeutic action of organic nitrates. The relatively stable analogue S-nitroso N-acetyl penicillamine (SNAP) is a potent vasodilator producing less pharmacologic tolerance than nitroglycerin upon prolonged administration. The therapeutic potential of this new class of vasodilators, however, may be limited by their chemical instability in solution (t1/2 of SNAP is 26 hr in 5% dextrose). We examined the usefulness of several cyclodextrins (CD) to stabilize this polar compound in solution. At cyclodextrin concentrations of 12 mM, hydroxypropyl-beta CD was most effective at stabilizing SNAP (t1/2 = 77 hr) when compared to alpha CD (41 hr), beta CD (69 hr), gamma CD (36 hr), and beta CD-tetradecasulfate (38 hr). Stability constants for the complexation of SNAP with the various cyclodextrins were determined by the classical solubility technique and were found to range from 26 to 435 M-1. Increased complexation brought about better SNAP stability. Complexation of SNAP with cyclodextrins, however, did not decrease the relaxation potency of SNAP as determined in an in vitro blood vessel preparation. Cyclodextrin complexation may be a useful approach to stabilize labile and polar compounds, such as S-nitrosothiols, without loss of pharmacologic activity.