title: Pulmonary Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] for the Treatment of Autoimmune Diseases.
abstract: HsTX1[R14A] is a potent and selective Kv1.3 channel blocker peptide with the potential to treat autoimmune diseases. Given the typically poor oral bioavailability of peptides, we evaluated pulmonary administration of HsTX1[R14A] in rats as an alternative route for systemic delivery. Plasma concentrations of HsTX1[R14A] were measured by liquid chromatography coupled with tandem mass spectrometry in rats receiving intratracheal administration of HsTX1[R14A] in solution (1-4 mg/kg) or a mannitol-based powder (1 mg/kg) and compared with plasma concentrations after intravenous administration (2 mg/kg). HsTX1[R14A] stability in rat plasma and lung tissue was also determined. HsTX1[R14A] was more stable in plasma than in lung homogenate, with more than 90% of the HsTX1[R14A] remaining intact after 5 h, compared with 40.5% remaining in lung homogenate. The terminal elimination half-life, total clearance, and volume of distribution of HsTX1[R14A] after intravenous administration were 79.6 ± 6.5 min, 8.3 ± 0.6 mL/min/kg, and 949.8 ± 71.0 mL/kg, respectively (mean ± SD). After intratracheal administration, HsTX1[R14A] in solution and dry powder was absorbed to a similar degree, with absolute bioavailability values of 39.2 ± 5.2% and 44.5 ± 12.5%, respectively. This study demonstrated that pulmonary administration is a promising alternative for systemically delivering HsTX1[R14A] for treating autoimmune diseases.
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Liang
authors: L
authors: Jin
authors: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907.
authors: Qi Tony
authors: QT
authors: Zhou
authors: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors: Hak-Kim
authors: HK
authors: Chan
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Ian C
authors: IC
authors: Larson
authors: Peptides International, Louisville, Kentucky 40299.
authors: Michael W
authors: MW
authors: Pennington
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Rodrigo A V
authors: RAV
authors: Morales
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Ben J
authors: BJ
authors: Boyd
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors: Raymond S
authors: RS
authors: Norton
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Electronic address: joseph.nicolazzo@monash.edu.
authors: Joseph A
authors: JA
authors: Nicolazzo
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C109471:TX1 toxin, Heterometrus spinnifer
keywords: epithelial delivery; peptides; pharmacokinetics; pulmonary absorption; pulmonary drug delivery