Preparation and evaluation of palmitic acid-conjugated exendin-4 with delayed absorption and prolonged circulation for longer hypoglycemia.
Albumin-binding achieved by fatty-acylation to drugs is considered to be an effective means of prolonging the circulation lifetimes of short-lived peptides. Here, exendin-4 was modified with palmitic acid, and the particle size and albumin-binding of palmitic acid-conjugated exendin-4 (Pal-Ex4) purified was investigated and visualized. Additionally, its pharmacokinetics and pharmacodynamics were evaluated in diabetic rodents. Pal-Ex4 had a greater molecular size (~125nm) and its albumin-binding was 5.6-fold that of Ex4. Molecular imaging showed that the subcutaneous absorption of Pal-Ex4 was delayed until 24h post-injection, whereas Ex4 was rapidly absorbed and distributed systemically. Pharmacokinetic and pharmacodynamic results confirmed these observations, for example, times to reach peak concentration and to achieve a blood glucose level nadir were greatly delayed versus Ex4, and the circulating half-life of Pal-Ex4 was much greater than that of Ex4. Consequently, the hypoglycemic degree of Pal-Ex4 (500 nmol/kg) was 4.2 fold greater than Ex4. Our results show that the extended hypoglycemic efficacy of Pal-Ex4 was due to (i) a delayed absorption due to micelle formation and (ii) an increased in vivo circulating half-life due to albumin-binding. We believe that this prototype of exendin-4 has considerable pharmaceutical potential as a systemic type 2 anti-diabetic treatment.
College of Pharmacy, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan, Republic of Korea.
Juho
J
Lee
Changkyu
C
Lee
Insoo
I
Kim
Hyung Ryong
HR
Moon
Tae Hyung
TH
Kim
Kyung Taek
KT
Oh
Eun Seong
ES
Lee
Kang Choon
KC
Lee
Yu Seok
YS
Youn
D000042:Absorption; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D000077270:Exenatide; D005215:Fasting / Q000378:metabolism; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008823:Micelles; D019308:Palmitic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010316:Particle Size; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012709:Serum Albumin / Q000737:chemistry; D014018:Tissue Distribution; D014688:Venoms / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D008823:Micelles; D010455:Peptides; D012709:Serum Albumin; D014688:Venoms; D019308:Palmitic Acid; D000077270:Exenatide