title: Pulmonary administered palmitic-acid modified exendin-4 peptide prolongs hypoglycemia in type 2 diabetic db/db mice.
abstract: Hypoglycemia caused by palmitic-acid modified exendin-4 (Pal-Ex4) administered via the pulmonary route was evaluated and compared with that caused by native Ex4. Pal-Ex4 and Ex4 in solution (each 50 μl) were administered using a microsprayer directly into the trachea of type 2 diabetic db/db mice at 75 or 150 nmol/kg. The lung depositions of Cy5.5-labeled Ex4 or Pal-Ex4 were monitored using an infrared imaging system after administration. The hypoglycemia caused by Pal-Ex4 was found to be 3.4 and 2.3 times greater than that caused by native Ex4 at 75 and 150 nmol/kg, respectively. Furthermore, time to blood glucose level (BGL) rebound to >150 mg/dl for Pal-Ex4 was 3.5 times greater than that of Ex4 (18.1 h vs. 5.2 h at 150 nmol/kg). In particular, the time taken for Pal-Ex4 to reach a BGL nadir was significantly greater than that of Ex4 (~8 h versus 4 h). Furthermore, lung deposition images clearly showed that Pal-Ex4 was slowly absorbed from lungs and barely distributed into kidneys until 8 h post-administration. It is likely that the prolonged hypoglycemia exhibited by Pal-Ex4 was due to; (i) delayed absorption in the lungs and (ii) albumin-binding in the circulation. The study demonstrates that palmitic acid-modified exendin-4 should be viewed as a long-acting inhalation candidate for the treatment of type 2 diabetes.
authors.affiliation: College of Pharmacy, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.
authors.forename: Juho
authors.initials: J
authors.lastname: Lee
authors.forename: Changkyu
authors.initials: C
authors.lastname: Lee
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Chi
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D007003:Hypoglycemia / Q000139:chemically induced* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D019308:Palmitic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D019308:Palmitic Acid; D000077270:Exenatide