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Antimicrobial Agents and Chemotherapy, October 2009, p. 4086-4095, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00419-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antiretroviral Tissue Kinetics: In Vivo Imaging Using Positron Emission Tomography{triangledown}

Michele Di Mascio,1* Sharat Srinivasula,2 Abesh Bhattacharjee,3 Lily Cheng,4 Lucia Martiniova,5 Peter Herscovitch,6 Juan Lertora,7 and Dale Kiesewetter8

Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Biostatistics Research Branch, SAIC—Frederick, Inc., NCI—Frederick, Frederick, Maryland 21702,2 Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892,3 Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,4 Reproductive and Adult Endocrinology Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,5 Positron Emission Tomography Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892,6 Clinical Pharmacology Program, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892,7 Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 208928

Received 27 March 2009/ Returned for modification 28 May 2009/ Accepted 31 July 2009

Our current knowledge on the antiviral efficacy, dosing, and toxicity of available highly active antiretroviral therapy regimens is mostly derived from plasma or blood kinetics of anti-human immunodeficiency virus (anti-HIV) drugs. However, the blood comprises only 2% of the total target cells in the body. Tissue drug levels may differ substantially from corresponding plasma levels, and drug distribution processes may be characterized by high intertissue variability, leading to suboptimal target site concentrations and the potential risk for therapeutic failures. Positron emission tomography has greatly expanded the scope of the pharmacokinetic measurements that can be performed noninvasively in animal models or humans. We have prepared [18F]FPMPA, a fluorine-18-radiolabeled analogue of tenofovir, to study antiretroviral tissue kinetics in vivo noninvasively and tested the imaging probe in rats. The biodistribution of the fluorine-18 analogue closely follows that of nonfluorinated tenofovir. Compared to that in the blood, the levels of penetration of the antiretroviral drug were found to be significantly reduced in the spleen and submandibular lymph nodes (~2-fold), in the mesenteric lymph nodes and the testes (~4-fold), and in the brain compartment (~25-fold). Intersubject variability of the trough drug concentration (measured at 120 min) in certain tissues, like the colon (coefficient of variation, >100%), is not reflected by the intersubject variability in the blood compartment (coefficient of variation, 24%). Positron emission tomography imaging of the fluorine-18 analogue revealed the accumulation of the antiretroviral drug in the cortex of the kidneys, a potential correlate of tenofovir-induced nephrotoxicity observed in HIV-1-infected treated patients. Thus, [18F]FPMPA is a promising radiotracer for evaluation of tenofovir biodistribution under carefully controlled drug administration protocols.

* Corresponding author. Mailing address: Division of Clinical Research, National Institue of Allergy and Infectious Diseases, National Institutes of Health, 6700B Rockledge Drive MSC 7609, Bethesda, MD 20892. Phone: (301) 451-5135. Fax: (301) 480-0912. E-mail: mdimascio{at}niaid.nih.gov

{triangledown} Published ahead of print on 10 August 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4086-4095, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00419-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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