Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol

Repeated oral administration of chemopreventive retinoids such as isotretin oin over extended periods of time is associated with intolerable systemic t oxicity. Here isotretinoin was formulated as a powder aerosol, and its deli very to the lungs of rats was studied with the aim to explore the possibili ty of minimizing adverse effects associated with its oral administration. R ats received isotretinoin orally (0.5, 1 or 10 mg kg(-1)) or by inhalation (theoretical dose similar to 1 or similar to 10 mg kg(-1)) in a nose-only i nhalation chamber. Isotretinoin was quantitated by high-pressure liquid chr omatography in plasma and lung tissue. The ratios of mean area of concentra tion-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma f or isotretinoin following single or repeated aerosol exposure surpassed tho se determined for the oral route by factors of between two (single low-dose ) and five (single high-dose). Similarly, the equivalent ratios for the max imal peak concentrations in lungs and plasma obtained after aerosol exposur e consistently exceeded those seen after oral administration, suggesting th at lungs were exposed to higher isotretinoin concentrations after aerosol i nhalation than after oral administration of similar doses. Repeated high do ses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is proba bly superior to its application via the oral route in terms of achieving ef ficacious drug concentrations in the lungs. (C) 2000 Cancer Research Campai gn.