Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery Journal Article

Authors: Brooks, A. D.; Tong, W.; Benedetti, F.; Kaneda, Y.; Miller, V.; Warrell, R. P. Jr
Article Title: Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery
Abstract: Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-transretinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5-17 h), lower peak serum concentrations (aerosol 71 ± 31 ng/ml, IT 68 ± 50 ng/ml), and lower liver levels (aerosol 111 ± 28 ng/g, IT 753 ± 350 ng/g) than the same dose administered IV (2 h, 838 ± 56 ng/ml, 4258 ± 1006 ng/g, respectively; P < 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing.
Keywords: controlled study; dose response; nonhuman; liver dysfunction; animals; animal tissue; lung disease; animal experiment; hypercalcemia; cancer inhibition; rat; lung; rats; drug bioavailability; drug blood level; rats, sprague-dawley; retinoic acid; hyperlipidemia; drug delivery system; drug formulation; chemoprevention; tretinoin; lung emphysema; aerosol; skeleton malformation; administration, inhalation; aerosols; all-trans-retinoic acid; human; male; priority journal; article; inhalers
Journal Title: Cancer Chemotherapy and Pharmacology
Volume: 46
Issue: 4
ISSN: 0344-5704
Publisher: Springer  
Date Published: 2000-10-01
Start Page: 313
End Page: 318
Language: English
PUBMED: 11052629
PROVIDER: scopus
DOI: 10.1007/s002800000148
Notes: Export Date: 18 November 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. William Ping-Yiu Tong
    158 Tong
  2. Ari D Brooks
    25 Brooks
  3. Vincent Miller
    270 Miller
  4. Raymond P Warrell
    167 Warrell