Nebulized cyclosporine in the rat - Assessment of regional lung and extrapulmonary deposition

Background. Nebulized cyclosporine (CsA) has been shown to limit lung allog raft rejection as well as intramuscular (IM) CsA, with limited blood diffus ion. The present study determined the pharmacokinetic parameters of nebuliz ed CsA, by the assessment of regional lung deposition and extrapulmonary di ffusion of CsA. Methods. CsA was given either by IM injection (10 mg/kg) or by aerosol (at 10 and 25 mg/kg doses); 70 rats were killed at 25 and 50 min, and at 2, 4, 6, 8, 12, 24, or 48 hr after CsA administration. CsA levels were measured i n the whole lung, in central and peripheral parts of the lung, in whole blo od, kidney, and heart, The areas under the concentration time curves (AUCs) were determined. Results. In blood, kidney, and heart, CsA levels were significantly higher for IM than for aerosol administrations at 10 and 25 mg/kg doses. In the wh ole lung, the AUC was greater for the aerosol route at 25 mg/kg doses (588 ng.hr/mg) than for the low-dose (200 ng.hr/mg) or IM administration (200 ng .hr/mg). The central to peripheral index of CsA (ratio of AUC central/perip heral part of the lung) was not significantly different for both aerosol ad ministrations (0.63 and 0.69, respectively) and for the IM route (0.81). Conclusions. Nebulized CsA allows better pulmonary concentration than IRI a dministration, with equivalent central and peripheral deposition whatever t he mode of administration, and results in lower levels in blood, kidney, an d heart.