title: Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: Oral delivery using pH-responsive nanoparticles vs. subcutaneous injection.
abstract: In this study, we report the biodistribution of aspart-insulin, a rapid-acting insulin analogue, following oral or subcutaneous (SC) administration to rats using the single-photon emission computed tomography (SPECT)/computed tomography (CT). Oral delivery of aspart-insulin was achieved using a pH-responsive nanoparticle (NP) system composed of chitosan (CS) and poly(gamma-glutamic acid). The results obtained in the SPECT/CT study indicate that the orally administered aspart-insulin was absorbed into the systemic circulation, while the drug carrier (CS) was mainly retained in the gastrointestinal tract.Via the SC route, the peak aspart-insulin concentration in the peripheral tissue/plasma was observed at 20 min after injection. Within 3 h, half of the initial dose (ID) of aspart-insulin was degraded and excreted into the urinary bladder. In contrast, via oral delivery, there was constantly circulating aspart-insulin in the peripheral tissue/plasma during the course of the study, while 20% of the ID of aspart-insulin was metabolized and excreted into the urinary bladder. In the pharmacodynamic (PD) and pharmacokinetic (PK) evaluation in a diabetic rat model, the orally administered aspart-insulin loaded NPs produced a slower hypoglycemic response for a prolonged period of time, whereas the SC injection of aspart-insulin produced a more pronounced hypoglycemic effect for a relatively shorter duration. Finally, comparison of the PD/PK profiles of the orally administered aspart-insulin with those of the SC injection of NPH-insulin, an intermediate-acting insulin preparation, suggests the suitability of our NP system to be used as a non-invasive alternative for the basal insulin therapy.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
authors.forename: Kiran
authors.initials: K
authors.lastname: Sonaje
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.forename: Shiaw-Pyng
authors.initials: SP
authors.lastname: Wey
authors.forename: Che-Kuan
authors.initials: CK
authors.lastname: Lin
authors.forename: Tzyy-Harn
authors.initials: TH
authors.lastname: Yeh
authors.forename: Ho-Ngoc
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Jyuhn-Huarng
authors.initials: JH
authors.lastname: Juang
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D016503:Drug Delivery Systems / Q000379:methods*; D017097:Electric Impedance; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D061267:Insulin Aspart; D008297:Male; D018613:Microscopy, Confocal; D023421:Models, Animal; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007328:Insulin; D061267:Insulin Aspart