T. Mizuma et al., Intestinal absorption and analgesic activity of aminopeptidase-resistant cellobiose-coupled leucine enkephalinamide, BIOPHARM DR, 19(9), 1998, pp. 605-610
Leucine enkephalinamide (LEamide), aminopeptidase-degradable opioid peptide
, was coupled with cellobiose (cellobiose-coupled LEamide, CcpLEamide). Ccp
LEamide was absorbed from the rat small intestine in vitro, whereas LEamide
was not. CcpLEamide on the mucosal side was more stable than aminopeptidas
e-resistant cellobiose-coupled leucine enkephalin (CcpLE) in the presence o
f inhibitors of enkephalinase and angiotensin converting enzyme, and much m
ore stable than LEamide. The absorption rate (clearance) of CcpLEamide was
comparable with that of CcpLE in the presence of these peptidase inhibitors
. Analgesic activities of these enkephalins were tested by the acetic acid
writhing assay and hot-plate assay after subcutaneous administration to mic
e. Both assays indicated CcpLEamide-induced analgesia. On the other hand, t
he analgesic activity of LEamide was not observed, but preheatment with ama
statin (a peptidase inhibitor) produced LEamide-induced analgesia. These re
sults indicate that CcpLEamide is stable in the body and has analgesic effe
cts without pretreatment with peptidase inhibitors, and was stable enough t
o be absorbed from the small intestine. We propose CcpLEamide as an orally
active analgesic peptide candidate. (C) 1998 John Wiley & Sons, Ltd.