The dose-related hypoglycemic effects of insulin emulsions incorporating highly purified EPA and DHA.
The dose-related pharmacological effects of insulin emulsion incorporating highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were investigated. Water-in-oil-in-water multiple emulsions (insulin dose, 0, 10, 25 and 50 IU/kg) incorporating 2% DHA or EPA were administered directly into the colonic and rectal loops in situ. Serum insulin levels rose and serum glucose levels decreased in an insulin dose-related fashion. The relationship of insulin dose and C(max) or AUC(insulin) was linear at the rectum, but a non-linear relationship was observed at the colon. The trend was more predominant in DHA. In the in vivo rectal absorption experiment using emulsions incorporating 2% DHA, 5 IU/kg of insulin emulsion produced a rapid, transitory increase in serum insulin levels and strong reduction of serum glucose levels. The pharmacological availability determined from the dose-response curve by s.c. administration of insulin reached 43.2+/-26.3% (mean+/-S.D.). Mucosal irritation caused by administration of emulsions incorporating 2% EPA or DHA was evaluated by a lactate dehydrogenase (LDH) release study, and compared with those of the emulsion incorporating 2% oleic or linolenic acid. Only when emulsion incorporating 2% oleic acid was applied in the intestine did significant LDH release into the mesenteric veins occur. Our results indicate that emulsion incorporating highly purified long-chain polyunsaturated fatty acid, especially DHA, has the potential of becoming the formulation for enteral delivery of insulin.
Morishita
M
M
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa-ku, 142 8501, Tokyo, Japan. morisita@hoshi.ac.jp
Kajita
M
M
Suzuki
A
A
Takayama
K
K
Chiba
Y
Y
Tokiwa
S
S
Nagai
T
T
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D004655:Emulsions; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007408:Intestinal Absorption; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D004655:Emulsions; D007004:Hypoglycemic Agents; D007328:Insulin; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D007770:L-Lactate Dehydrogenase; D005947:Glucose