title: Antiretroviral tissue kinetics: in vivo imaging using positron emission tomography.
abstract: 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 (approximately 2-fold), in the mesenteric lymph nodes and the testes (approximately 4-fold), and in the brain compartment (approximately 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.
authors: Division of Clinical Research, Biostatistics Research Branch, National Institue of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mdimascio@niaid.nih.gov
authors: Michele
authors: M
authors: Di Mascio
authors: Sharat
authors: S
authors: Srinivasula
authors: Abesh
authors: A
authors: Bhattacharjee
authors: Lily
authors: L
authors: Cheng
authors: Lucia
authors: L
authors: Martiniova
authors: Peter
authors: P
authors: Herscovitch
authors: Juan
authors: J
authors: Lertora
authors: Dale
authors: D
authors: Kiesewetter
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D001921:Brain / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D005462:Fluorine Radioisotopes; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068698:Tenofovir; D013737:Testis / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D005462:Fluorine Radioisotopes; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine