This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Verma, R. K.
Right arrow Articles by Misra, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Verma, R. K.
Right arrow Articles by Misra, A.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*ISONIAZID
*RIFABUTIN

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2008, p. 3195-3201, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00153-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Intracellular Time Course, Pharmacokinetics, and Biodistribution of Isoniazid and Rifabutin following Pulmonary Delivery of Inhalable Microparticles to Mice{triangledown}

Rahul Kumar Verma, Jatinder Kaur, Kaushlendra Kumar, Awadh Bihari Yadav, and Amit Misra*

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

Received 4 February 2008/ Returned for modification 29 April 2008/ Accepted 23 June 2008

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 inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (~1.4 and 1.1 µg/106 cells) and rifabutin (~2 µg/ml and ~1.4 µg/106 cells) within 10 min. Microparticles maintained the 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 inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 µg of either drug, to parallel groups): isoniazid, serum half-life (t1/2) = 18.63 ± 5.89 h (3.91 ± 1.06 h), maximum concentration in serum (Cmax) = 2.37 ± 0.23 µg·ml–1 (3.24 ± 0.57 µg·ml–1), area under the concentration-time curve from 0 to 24 h (AUC0-24) = 55.34 ± 13.72 µg/ml–1 h–1 (16.64 ± 1.80 µg/ml–1 h–1), and clearance (CL) = 63.90 ± 13.32 ml·h–1 (4.43 ± 1.85 ml·h–1); rifabutin, t1/2 = 119.49 ± 29.62 h (20.18 ± 4.02 h), Cmax = 1.59 ± 0.01 µg·ml–1 (3.47 ± 0.33 µg·ml–1), AUC0-96 = 109.35 ± 14.78 µg/ml–1 h–1 (90.82 ± 7.46 µg/ml–1 h–1), and CL = 11.68 ± 7.00 ml·h–1 (1.03 ± 0.11 ml·h–1). 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.

* Corresponding author. Mailing address: Pharmaceutics Division, Central Drug Research Institute, Chhattar Manzil Palace, Lucknow 226001, India. Phone: (91)-(522)-261-2411, ext. 4302. Fax: (91)-(522)-262-3405. E-mail: amit.cdri{at}gmail.com

{triangledown} Published ahead of print on 30 June 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3195-3201, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00153-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»