title: Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages.
abstract: Microparticles prepared by the precipitation with a compressed antisolvent (PCA) process were evaluated for their potential in targeting an ionizable prodrug of isoniazid (INH), isoniazid methanesulfonate (INHMS), for sustained delivery of INH to alveolar macrophages (AMs). The charged prodrug was ion-paired with two different hydrophobic cations (tetrapentylammonium (TPA)- and tetraheptylammonium (THA)-bromide), and loaded separately into the poly(l-lactide) (PLA) microparticles. The drug/polymer particles were spherical in shape and between 1 and 3 mum in diameter. The choice of hydrophobic cations did not affect drug incorporation efficiencies or the release kinetics of INH from the microparticles. Using a sensitive liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay developed for INH, high level of INH was detected in NR8383, a rat AM cell line, following exposure of these cells to drug-loaded microparticles. To confirm the microparticles can target AMs in vivo, we compared the INH levels in lavaged bronchoalveolar macrophages by LC-MS/MS after the Sprague-Dawley rats were administered either INHMS in PLA microparticles by intra-tracheal instillation or INH solution by gavage or intra-tracheal instillation. As expected, only microparticles provided sustained and targeted delivery of INH to AMs. Most importantly, this method of delivery led to substantial reduction in the blood levels of acetylisoniazid (AcINH), a major and potential toxic metabolite of INH.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Campus Box C238, Denver, CO 80262, USA.
authors: Huiyu
authors: H
authors: Zhou
authors: Yanling
authors: Y
authors: Zhang
authors: Danielle L
authors: DL
authors: Biggs
authors: Mark C
authors: MC
authors: Manning
authors: Theodore W
authors: TW
authors: Randolph
authors: Uwe
authors: U
authors: Christians
authors: Brooks M
authors: BM
authors: Hybertson
authors: Ka-yun
authors: KY
authors: Ng
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D003692:Delayed-Action Preparations; D004339:Drug Compounding; D016503:Drug Delivery Systems; D007538:Isoniazid / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D008168:Lung / Q000187:drug effects*; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D008855:Microscopy, Electron, Scanning; D049329:Nanostructures; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000995:Antitubercular Agents; D003692:Delayed-Action Preparations; D007538:Isoniazid