title: In the lung aerosol cyclosporine provides a regional concentration advantage over intramuscular cyclosporine.
abstract: BACKGROUND
  Acute rejection remains an almost universal complication among lung transplant recipients. Refractory rejection as well as chronic systemic immunosuppression is associated with significant morbidity and mortality. Recent studies suggest that aerosol cyclosporine may address these issues by effectively preventing acute cellular rejection while maintaining low systemic drug concentrations. This study was designed to evaluate the concentrations of cyclosporine in blood and lung tissue after aerosol and intramuscular administration.
  
  
  METHODS
  Lewis rats were divided into 4 experimental groups: Groups A (n = 33) and B (n = 30) received aerosol cyclosporine 3 and 5 mg/kg, respectively; Groups C (n = 33) and D (n = 30) received systemic cyclosporine 5 and 15 mg/kg, respectively. We used high-performance liquid chromatography to quantitate blood and lung tissue cyclosporine levels at timed intervals. We used the trapezoidal rule to approximate area under the concentration vs time curve (AUC).
  
  
  RESULTS
  Aerosol delivery of cyclosporine resulted in higher and more rapid peak drug levels in lung tissue samples than did systemic delivery. At an equivalent 5 mg/kg dose, the cyclosporine AUC was 3 times higher with aerosol delivery than with intramuscular delivery in lung tissue (477,965 vs 157,706 ng x hour/g, respectively). The lung tissue: blood AUC ratio was highest in the aerosol groups (27.3:1 and 17.4:1) compared with the intramuscular groups (8.1:1 and 9.4:1).
  
  
  CONCLUSIONS
  Local aerosol inhalation delivery of cyclosporine provides a regional advantage over systemic intramuscular therapy by providing higher peak concentrations and greater lung tissue exposure.
authors.affiliation: Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Mitruka
authors.forename: A
authors.initials: A
authors.lastname: Won
authors.forename: K R
authors.initials: KR
authors.lastname: McCurry
authors.forename: A
authors.initials: A
authors.lastname: Zeevi
authors.forename: T
authors.initials: T
authors.lastname: McKaveney
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: A
authors.initials: A
authors.lastname: Iacono
authors.forename: B P
authors.initials: BP
authors.lastname: Griffith
authors.forename: G J
authors.initials: GJ
authors.lastname: Burckart
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007273:Injections, Intramuscular; D008168:Lung / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D007166:Immunosuppressive Agents; D016572:Cyclosporine