In this study, the stability in and transport across a cell culture model of the blood-brain barrier (BBB) is investigated for leucine-enkephalin (Leu-enkephalin) and four 4-imidazolidinone prodrugs of Leu-enkephalin. The results show that Leu-enkephalin is degraded in the cell culture model of the BBB both by cytosolic and plasma membrane bound enzymes. It is likely that aminopeptidase is the predominant enzyme responsible for the degradation of Leu-enkephalin. All four 4-imidazolidinone prodrugs of Leu-enkephalin examined showed an increased stability of Leu-enkephalin against degradation by both plasma membrane bound and cytosolic enzymes. Consequently, the transport properties of Leu-enkephalin is also improved by up to 60% by formation of 4-imidazolidinone prodrugs. Copyright (C) 1998 Elsvier Science B.V.