The glucose-lowering potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo.
Exendin-4 is a potent insulinotropic agent in diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. In this study, an orally available exendin-4 formulation, using an enteric-coated capsule containing pH-responsive NPs, was developed. Following oral administration of (123)I-labeled-exendin-4 loaded NPs in rats, the biodistribution of the administered drug was investigated using a dual isotope dynamic SPECT/CT scanner. The results showed that the radioactivity of (123)I-exendin-4 propagated from the esophagus, stomach, and small intestine and then was absorbed into the systemic circulation; with time progressing, (123)I-exendin-4 was metabolized and excreted into the urinary bladder. In the in vivo dissolution study, it was found that the enteric-coated capsule remained intact while in the stomach; the capsule was completely dissolved in the proximal segment of the small intestine and the loaded contents were then released. Oral administration of the capsule containing exendin-4 loaded NPs showed a maximum plasma concentration at 5 h after treatment; the bioavailability, relative to its subcutaneous counterpart, was found to be 14.0 ± 1.8%. The absorbed exendin-4 could then stimulate the insulin secretion and provide a prolonged glucose-lowering effect. The aforementioned results suggest that the orally available exendin-4 formulation developed warrants further exploration as a potential therapy for diabetic patients.
Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
Ho-Ngoc
HN
Nguyen
Shiaw-Pyng
SP
Wey
Jyuhn-Huarng
JH
Juang
Kiran
K
Sonaje
Yi-Cheng
YC
Ho
Er-Yuan
EY
Chuang
Chia-Wei
CW
Hsu
Tzu-Chen
TC
Yen
Kun-Ju
KJ
Lin
Hsing-Wen
HW
Sung
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D016503:Drug Delivery Systems / Q000379:methods*; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000077270:Exenatide; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007279:Injections, Subcutaneous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility / Q000187:drug effects; D055672:Static Electricity; D013608:Tablets, Enteric-Coated / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051598:Whole Body Imaging
D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014677:Pharmaceutical Vehicles; D013608:Tablets, Enteric-Coated; D014688:Venoms; D000077270:Exenatide