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

Abstract

Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg–1) or by inhalation (theoretical dose ~1 or ~10 mg kg–1) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses 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 probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs. © 2000 Cancer Research Campaign

INHALATION ADMINISTRATION OF ALL-TRANS-RETINOIC ACID FOR TREATMENT OF ELASTASE-INDUCED PULMONARY EMPHYSEMA IN FISCHER 344 RATS

“…Inhaled retinoids have been proposed as chemopreventatives for cancer of the lung and aerodigestive tract [25][26][27][28][29]. Inhaled 13-cis-retinoic acid (cRA) in rats has been shown to up-regulate biomarkers of retinoid activity in the lung and to have no effect on biomarkers in the liver, whereas dietary cRA does just the opposite [29].…”

“…Thus, retinoid bioactivity and potential pharmacologic activity is localized to the lung by inhalation delivery more than by oral administration. Although inhalation delivery has been shown to be better than oral administration for targeting the lung [28], there are likely limitations due to toxicity in inhaled doses that may be used. Rats in the present study developed localized epidermal toxicity when exposed nose-only to the high dose of ATRA (500 mg/m 3 ) and had a significant 12% to 13% decrease in BW attributed to decreased feed intake over the 3-week treatment period (Figure 2).…”

Effects of tracheal occlusion with retinoic acid administration on normal lung development

“…Absence of RA detected in lung tissue at 4 days after injection was due to the short half-life of RA in vivo. 46 It also underlines that the duration of RA exposure is relatively short after a single bolus injection. Indeed, even if the animal model and the administration were different, a previous study reported that after a single bolus administration, RA was not detectable in the lung tissue after 24 h. 46 In conclusion, the observations reported here indicate that the most appropriate RA vehicle for intratracheal injection seemed liposomes, with potential effect on surfactant production.…”

Uptake of all-transretinoic acid–containing aerosol by inhalation to lungs in a guinea pig model system—A pilot study

“…Experiments with inhalable RA formulations have been reported by Dahl et al [9], Wang et al [10], and Raleigh et al [30] using mice and rats. In those studies, nebulizing solutions consisted of either ethanolic solutions of 13- cis RA [9, 10] or a polyethylene glycol 300/ethanol-based mixture, using a PARI LC Star nebulizer.…”

“…In those studies, nebulizing solutions consisted of either ethanolic solutions of 13- cis RA [9, 10] or a polyethylene glycol 300/ethanol-based mixture, using a PARI LC Star nebulizer. In Raleigh et al [30], aerosol formation was achieved with powdered 13- cis RA, dispersed with air. Brooks et al [31] used a metered dose inhaler with hydrofluoroalkane 134a as propellant.…”