title: [Hypoglycemic effect and enhanced gastrointestinal absorption of insulin using new cinnamoyl-phenylalanine derivatives].
abstract: To find a new adjuvant for oral administration of Insulin (IN), we examined the gastrointestinal absorption and hypoglycemic effect of new IN-Cinnamoyl (Cin)-Phenylalanine (Phe) derivative preparations administered orally or intraduodenally to fasted normal and Streptozotocin (STZ)-diabetic animals. Selected IN.N-alpha-Chlorocinnamoyl-D-Phenylalanine (A-3989) and IN.N-alpha-Chloro-4-methyl-cinnamoyl-D-phenylalanine (A-4266) preparations among 80 of IN.Cin-Phe derivative preparations administered orally or intraduodenally promoted absorption of IN from the gastrointestinal tract resulting in significantly elevated serum IN levels and reduced serum glucose levels in fasted normal and Streptozotocin (STZ)-diabetic animals. Especially, IN.A-3989(25U.150mg/kg) and IN.A-4266(12.5U.150mg/kg) preparation administered intraduodenally represented marked enhanced IN absorption in normal mice and area under the serum IN concentration vs. time curve (AUC) showed 97.5 and 49.3 (mU.min/ml), respectively. Furthermore, A-3989 and A-4266 were found to exert inhibitory effect on IN degradation by partially purified mouse intestinal enzyme. IN.A-4266 (25U.200mg/kg) preparation administered orally before D-glucose (2g/kg) loading the significant elevation of serum IN levels and improvement of impaired glucose tolerance (IGT) in STZ-diabetic mice. Thus, these findings suggest that effective oral administration of new In.Cin-Phe derivative preparations with dosage form design, such as enteric coating form, may become feasible in diabetic patients.
authors.affiliation: Department of Pharmacy, Hokkaido University Hospital, Hokkaido University, School of Medicine, Sapporo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fukushima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D005260:Female; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D002934:Cinnamates; D007328:Insulin; D010649:Phenylalanine; D013311:Streptozocin