title: Pharmacokinetics, Metabolism, and Partial Biodistribution of "Pincer Therapeutic" Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles.
abstract: Nitazoxanide (NTZ) induces autophagy in mammalian cells and also has mycobactericidal activity, displaying a two-pronged therapeutic effect, on the host as well as the pathogen. The pharmacokinetics and biodistribution of inhaled NTZ were investigated. Particles containing NTZ in a matrix of PLGA were prepared by spray drying. HPLC and LC-MS/MS methods were developed and validated. Particles were administered as inhalations to mice. Drug concentrations in plasma and tissues were estimated at different time points. Drug loading (∼36%), entrapment efficiency (>90%), and the conversion of NTZ into metabolites in plasma and lung homogenates were assessed satisfactorily by HPLC. NTZ pharmacokinetics and biodistribution following intravenous administration or inhalation were established by LC-MS. NTZ converted into tizoxanide (99% in 30 min) and other metabolites. Pulmonary delivery of NTZ entrapped in particles increased the half-life of the drug by factors of 3, 12, and 200 in the plasma, lung tissue, and alveolar macrophages, respectively. Targeted delivery and prolonged lung retention along with dose sparing of the kidneys was observed upon pulmonary delivery as compared to intravenous administration.
authors.affiliation: CSIR-Central Drug Research Institute , Sector 10A, Janakipuram Extension, Mohiuddinpur, Lucknow 226031, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: CSIR-Central Drug Research Institute , Sector 10A, Janakipuram Extension, Mohiuddinpur, Lucknow 226031, India.
authors.forename: Sachin L
authors.initials: SL
authors.lastname: Tulsankar
authors.affiliation: CSIR-Central Drug Research Institute , Sector 10A, Janakipuram Extension, Mohiuddinpur, Lucknow 226031, India.
authors.forename: Rabi S
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: CSIR-Central Drug Research Institute , Sector 10A, Janakipuram Extension, Mohiuddinpur, Lucknow 226031, India.
authors.forename: Amit
authors.identifier: 0000-0001-5503-0694
authors.initials: A
authors.lastname: Misra
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D058995:Dry Powder Inhalers / Q000379:methods; D006207:Half-Life; D019344:Lactic Acid / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D009574:Nitro Compounds; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D053719:Tandem Mass Spectrometry / Q000379:methods; D013844:Thiazoles / Q000378:metabolism* / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D009574:Nitro Compounds; D013844:Thiazoles; C104067:tizoxanide; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C041747:nitazoxanide
keywords: HPLC; LC−MS; dry powder inhalation; one-compartment; tizoxanide