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INTRANASAL DELIVERY OF RECOMBINANT HUMAN PARATHYROID HORMONE [HPTH (1–34)], TERIPARATIDE IN RATS.
Agu1, R.U., Valiveti1, S., Earles1, D.C., Klausner2, M., Hayden2, P.J., Wermeling1,3,D.P., Stinchcomb1, A.L.
1College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA; 2MatTek Corporation, Ashland, Massachusetts, USA; 3Intranasal Technology, Inc., Lexington, Kentucky, USA.
Endocrine Research, 30, (3), 455-467, (2004).
Keywords: Chronic toxicity, EpiAirway, Epithelium permeation, Human parathyroid hormone [hPTH (1-34)], Interanimal variability , Intranasal absorption, Mucociliary clearance, Nasal absorption, Nasal administration, Nasal permeability, Nasal tissue, Nasal toxicity, Oral delivery studies, Organotypic model, Permeability , Pharmacokinetics, Protein leakage, Salmon-calcitonin, Subcutaneous injection, TEER, Teriparatide , Tissue viability, Toxicity , Tracheal/bronchial epithelial cells
Endpoints: MTT assay, Potential difference (PD), TEER
Materials Tested: Human parathyroid hormone [hPTH (1-34)]
Summary: The aim of this study was to explore the nasal route as an alternative to daily sub-cutaneous injections of hPTH (1–34). Anesthetized rats were surgically prepared and nasally dosed with aqueous solutions of hPTH (1–34). Plasma samples were assayed by radioimmunoassay and data generated fit to two- (intravenous) and one- (intranasal) compartment pharmacokinetic models using WinNonlin®. The toxicity of hPTH (1–34) solution administered to the rats was assessed by screening its effect on transepithelial electrical resistance, potential difference, paracellular marker permeation, tissue viability, and protein leakage using the EpiAirway™ tissue model. The intranasal absorption of hPTH (1–34) was rapid; the absorption rate constants (α) were 33.2 ± 24 h-1 [without bovine serum albumin (BSA)] and 9.8 ± 5.1 h-1 (with 1% BSA). The maximum plasma concentrations (Cmax): 151 ± 24 pg/mL (without BSA) and 176 ± 37 (with 1% BSA) were attained within approximately 15 min. The intranasal bioavailabilities (Fabs) were 12.1 ± 3.4% (without BSA) and 17.6 ± 1.5% (with 1% BSA). The hPTH (1–34) formulation administered to the rats had no detrimental effect on the EpiAirway® tissue epithelial electrical parameters and functional integrity. Based on the results of this study, the nasal route appears to be a prospective alternative to subcutaneous injections of hPTH (1–34).
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