To the Editor: The supplementation of uridine prevents and treats the mitochondrial toxicity of pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) by abrogating mitochondrial DNA (mtDNA) depletion in vitro1-3 and in vivo.4-6 Uridine completely abrogates the lipoatrophic phenotype of adipocytes exposed to zidovudine and stavudine by preventing apoptosis, loss of lipids, mtDNA depletion, and mitochondrial depolarization.1 Uridine also normalizes the proliferation of blood cell precursors exposed to zidovudine.3 A recent randomized, double-blind, and placebo-controlled trial of dietary uridine supplementation demonstrated a markedly rapid and quantitatively significant gain of subcutaneous fat in HIV-infected lipoatrophic subjects under continued treatment with thymidine analogues.4 NucleomaxX (Pharma Nord, Vojens, Denmark) is a food supplement that has a high bioavailability of uridine.7 Product analysis revealed that each 36-g sachet of NucleomaxX contains 1.61% of uridine and 15.0% of 2′,3′,5′-tri-O-acetyluridine, the latter of which can be converted to uridine by plasma esterases.8 Previous studies have shown that compared with pure uridine, 2′,3′,5′-tri-O-acetyluridine exhibits enhanced gastrointestinal tract absorption and is resistant to catabolism by uridine phosphorylase.9 The beneficial effects of uridine were dose dependent and observed at concentrations of 50 to 200 μM, depending on the system studied.1-3 Competition of uridine or its metabolites with NRTIs at polymerase-γ or at enzymes responsible for NRTI activation and transport is the most plausible mechanism of action.2 Such a competitive mechanism, however, also raises the question about the safety of uridine supplementation in HIV-infected patients. Whereas interference of uridine with the antiretroviral efficacy of NRTIs at the intracellular level is unlikely based on phenotypic HIV resistance assays,10 it has not yet been examined whether uridine interferes with competitive processes involved in the gastrointestinal absorption or plasma elimination of pyrimidine NRTIs. The purpose of this study was therefore to assess the effect of uridine supplementation on the pharmacokinetic profile of lamivudine and zidovudine. After ethics committee approval and informed written consent, healthy fasting adult human volunteers (4 male and 4 female, mean body weight of 69.9 ± 9.0 kg) took 1 tablet of zidovudine/lamivudine (300 mg/150 mg) and 2 NRTIs (in a fixed-dose combination [FDC]) that are both pyrimidine analogues. After an 8-day wash-out period, the probands swallowed another tablet of zidovudine/lamivudine (FDC) and simultaneously consumed 36 g of NucleomaxX (1 sachet) dissolved in 200 mL of orange juice. Proband sera were assayed for NRTI concentrations by high-performance liquid chromatography/ultraviolet detection using a Symmetry Octyl 15-cm column (Waters, Milford, MA) with a phosphate buffer/acetonitrile mobile phase. Without uridine supplementation, zidovudine and lamivudine serum levels rose sharply after ingestion of the tablet and peaked after 0.91 hour (SEM = 0.20) and 1.66 hours (SEM = 0.09), respectively (Fig. 1). The mean maximal serum concentration (Cmax) was 1.53 μg/mL (SEM = 0.27) for zidovudine and 1.21 μg/mL (SEM = 0.14) for lamivudine. The mean Cmax of zidovudine was similar in men (1.59 μg/mL) and women (1.48 μg/mL) (P = 0.91). The mean Cmax for lamivudine was 1.05 μg/mL in men and 1.37 μg/mL in women (P = 0.53). Zidovudine was eliminated from the serum with a half-life of 1.0 hour (SEM = 0.12), whereas the half-life of lamivudine was 4.1 hours (SEM = 0.81). There was no significant difference in the elimination time between men and women. The mean AUC0-∞ for zidovudine, calculated with the linear trapezoidal rule between the time points in the time data range, was 2.02 μg/mL × h (SEM = 0.29). The mean area under the curve from zero to infinity (AUC0-∞) for lamivudine was 4.95 μg/mL × h (SEM = 0.88). The pharmacokinetic findings for lamivudine and zidovudine in this study of healthy subjects are consistent with those observed in previous zidovudine/lamivudine FDC studies.11,12FIGURE 1: Lamivudine and zidovudine serum concentrations after consumption of 1 tablet of lamivudine/zidovudine combination with or without simultaneous oral uridine supplementation with NucleomaxX (1 36-g sachet). Data are mean ± SEM.Coadministration of NucleomaxX did not significantly affect any of the pharmacokinetic parameters of zidovudine. Lamivudine Cmax values were significantly higher (P = 0.01) and peaked faster (time to maximum concentration [tmax]; P = 0.02) after NucleomaxX coadministration, but there were no significant differences in the AUC0-∞ or half-life. Adverse events were not observed. We conclude that NucleomaxX does not negatively affect the bioavailability of lamivudine and zidovudine. These safety results, the so far sustained HIV suppression in clinical studies,4,5,13 and the efficacy data provide the rationale for a currently recruiting phase 3 trial of NucleomaxX in lipoatrophy. Nils Venhoff, MD* Ana C. Venhoff, PhD* Anura L. Jayewardene, PhD† Fran Aweeka, PharmD† Dirk Lebrecht, PhD* Ulrich A. Walker, MD* *Department of Rheumatology and Clinical Immunology Medizinische Universitätsklinik Freiburg, Germany †Drug Research Unit Department of Clinical Pharmacy School of Pharmacy University of California, San Francisco San Francisco, CA