title: Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration.
abstract: OBJECTIVE
  To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs.
  
  
  METHODS
  Deposition and distribution of (99m)pertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin.
  
  
  RESULTS
  Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour.
  
  
  CONCLUSIONS
  TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.
authors.affiliation: MannKind Corporation, Valencia, California, USA. jcassidy@mannkindcorp.com
authors.forename: James P
authors.initials: JP
authors.lastname: Cassidy
authors.forename: Nikhil
authors.initials: N
authors.lastname: Amin
authors.forename: Mark
authors.initials: M
authors.lastname: Marino
authors.forename: Mark
authors.initials: M
authors.lastname: Gotfried
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Knut
authors.initials: K
authors.lastname: Sommerer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baughman
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D005260:Female; D005650:Fumarates / Q000032:analysis / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D010879:Piperazines / Q000032:analysis / Q000493:pharmacokinetics; D011208:Powders; D011877:Radionuclide Imaging; D013670:Sodium Pertechnetate Tc 99m / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D005650:Fumarates; D007004:Hypoglycemic Agents; D007328:Insulin; D010879:Piperazines; D011208:Powders; D013670:Sodium Pertechnetate Tc 99m; C413290:3,6-bis(N-fumaryl-N(n-butyl)amino)-2,5-diketopiperazine