title: Partial biodistribution and pharmacokinetics of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to rhesus macaques.
abstract: Dry powder inhalations (DPI) of microparticles containing isoniazid (INH) and rifabutin (RFB) are under preclinical development for use in pulmonary tuberculosis. Microparticles containing 0.25, 2.5, or 25 mg of each drug were administered daily for 90 days to rhesus macaques (n = 4/group). Single inhalations or intravenous (i.v.) doses were administered to separate groups. Drugs in serum, alveolar macrophages, and organ homogenates were assayed by high-performance liquid chromatography (HPLC). The RFB/INH in the lungs (101.10 ± 12.90/101.07 ± 8.09 μg/g of tissue) was twice that of the liver concentrations (60.22 ± 04.97/52.08 ± 4.62 μg/g) and four times that of the kidneys (22.89 ± 05.22/30.25 ± 3.71 μg/g). Pharmacokinetic parameters indicated the operation of flip-flop kinetics. Thus, the elimination half-life (t(1/2)) of RFB and INH was calculated as 8.01 ± 0.5 and 2.49 ± 0.23 h, respectively, upon intravenous (iv) administration, and as 13.8 ± 0.8 and 10.43 ± 0.77 h following a single inhalation; or 13.36 ± 3.51 and 10.13 ± 3.01 at a presumed steady state (day 60 of dosing). Targeted and sustained drug delivery to nonhuman primate lungs and alveolar macrophages was demonstrated. Flip-flop serum pharmacokinetics was observed, and nonlinearity in some pharmacokinetic parameters at logarithmic dose increments was indicated. The results suggest that human patients would benefit through improvement in biodistribution following DPI.
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar Verma
authors.forename: Jatinder Kaur
authors.initials: JK
authors.lastname: Mukker
authors.forename: Ravi Shankar Prasad
authors.initials: RS
authors.lastname: Singh
authors.forename: Kaushlendra
authors.initials: K
authors.lastname: Kumar
authors.forename: Priya Ranjan Prasad
authors.initials: PR
authors.lastname: Verma
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D000818:Animals; D007538:Isoniazid / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism*; D008253:Macaca mulatta; D017828:Rifabutin / Q000493:pharmacokinetics*
chemical_list: D017828:Rifabutin; D007538:Isoniazid