Background:  Antiviral efficacy, dosing, and toxicity of current regimens are mostly derived from plasma or blood kinetics of anti-HIV drugs. However, the blood comprises only 2% of total target cells in the body. Drug penetration may vary in anatomic compartments and among subjects. In addition to viral resistance, prolonged antiviral treatment may affect mechanisms of drug retention in the host cells that can diminish efficacy over time. Sub-optimal therapy in tissues has been postulated as possible cause of therapy failure, however little is known about drug distribution in tissues (especially in longitudinal analyses), mainly due to target tissues inaccessibility. Here, we describe the tissue drug kinetics of the NRTI tenofovir (R-PMPA) and its ¹⁸F-radiolabeled analogue (S-FPMPA), a potential ligand for positron emission tomography (PET) imaging

Methods:  The synthesis and radiofluorination of the analogue followed literature precedent. S-FPMPA inhibitory activity was determined in MT4 cells infected with simian-human immunodeficiency virus (SHIV). To confirm the similarity of biodistribution between the 2 analogues, we have performed a study in rats with dual labeling. We dissected 12 rats at 4 time-points after intravenous co-injection of unlabeled PMPA (5 mg/kg), ¹⁴C -PMPA (5 µCi) and ¹⁸F -PMPA (200 µCi)  

Results:  The products of radio-synthesis had high radiochemical and enantiomeric purity.  S-FPMPA showed inhibitory activity of viral replication with an IC₅₀ of 1.85 µM, similar to R-PMPA. For in vivo biodistribution, data (see the figure) show good overlapping of ¹⁴C -PMPA and ¹⁸F -FPMPA kinetics in several organs. The similarity in femur uptake (tissue with high avidity for unbound fluoride), suggested that ¹⁸F-fluoride is not a metabolite of F-PMPA. Intra-subject variability of the drug trough concentration in certain tissues (jejunum, Peyer’s patches > 60%) is not revealed by the blood compartment (10%). Kinetics in kidney show drug accumulation, which might be associated to tenofovir-induced nephrotoxicity

Conclusion:  S-¹⁸F -FPMPA is a candidate imaging probe for the distribution of tenofovir in tissues in vivo. Drug penetration varies between anatomic compartments and subjects. Potential areas of animal research and clinical investigation that could benefit from this technique are: longitudinal analysis of drug kinetics during chronic treatment; drug interactions; drug volume of distribution after topical administration in microbicide studies; and generalization of the concept of antiviral efficacy