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Antimicrob. Agents Chemother. doi:10.1128/AAC.00153-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Intracellular time-course, pharmacokinetics and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice

Pharmaceutics Division, Central Drug Research Institute, Chhattar Manzil Palace, Lucknow, 226001 India

^* To whom correspondence should be addressed. Email: amit.cdri{at}gmail.com.

	Abstract

Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon administration of inhalations of microparticles or intravenous administration of free drugs to mice was investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (1.4 and 1.1 µg/10⁶ cells) and rifabutin (2µg/ml and 1.4 µg/10⁶ cells) within 10 min. Microparticles maintained intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin® from samples obtained after administration of inhalations using an in-house apparatus (figures in parantheses refer to parameters obtained after intravenous administration of equivalent amounts, i.e., 100µg of either drug, to parallel groups). Isoniazid: t= 18.63±5.89 (3.91±1.06) h; Cmax= 2.37±0.23 (3.24±0.57) µg.ml^-1; AUC_0-24h= 55.34±13.72 (16.64±1.80) µg/ml^-1hr^-1; and Cl= 63.90±13.32 (4.43±1.85) ml.h^-1. Rifabutin: t= 119.49±29.62 (20.18±4.02); Cmax= 1.59±0.01 (3.47±0.33); AUC_0-96h= 109.35±14.78 (90.82±7.46) and Cl= 11.68±7.00 (1.03±0.11). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.