Enhanced Uridine Bioavailability Following Administration of a Triacetyluridine-Rich Nutritional Supplement

Melissa E Weinberg,Ulrich A Walker,Mark C Roman,Peyton Jacob,Morris Schambelan,Michael Wen,Kathleen Mulligan,Polly Cheung,Wen-Liang Zhou

doi:10.1371/journal.pone.0014709

Abstract

BackgroundUridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. Historically, the use of uridine as a therapeutic agent has been limited by poor bioavailability. A food supplement containing nucleosides, NucleomaxX®, has been reported to raise plasma uridine to supraphysiologic levels.Methodology/Principal FindingsSingle- and multi-dose PK studies following NucleomaxX® were compared to single-dose PK studies of equimolar doses of pure uridine in healthy human volunteers. Product analysis documented that more than 90% of the nucleoside component of NucleomaxX® is in the form of triacetyluridine (TAU). Single and repeated dosing with NucleomaxX® resulted in peak plasma uridine concentrations 1–2 hours later of 150.9±39.3 µM and 161.4±31.5 µM, respectively, levels known to ameliorate mitochondrial toxicity in vitro. Cmax and AUC were four-fold higher after a single dose of NucleomaxX® than after uridine. No adverse effects of either treatment were observed.Conclusions/SignificanceNucleomaxX®, containing predominantly TAU, has significantly greater bioavailability than pure uridine in human subjects and may be useful in the management of mitochondrial toxicity.

Highlights

Uridine, a pyrimidine nucleoside that plays an essential role in the synthesis of RNA and other key physiologic processes [1], has been used as a treatment for patients with hereditary orotic aciduria for more than four decades
These results suggest that the formulation of uridine in NucleomaxXH may have enhanced bioavailability, the differences in plasma uridine levels achieved in studies of uridine and those of NucleomaxxH could be explained by the fact that different analytic techniques and study designs were employed
The half-life for pure uridine was longer than that for NucleomaxXH (4.661.2 vs. 3.460.8 hours, p = 0.05). Both single and repeated dosing with NucleomaxXH resulted in peak plasma uridine concentrations .150 mM, levels known to ameliorate mitochondrial toxicity in vitro, without any adverse effects

Summary

Introduction

A pyrimidine nucleoside that plays an essential role in the synthesis of RNA and other key physiologic processes [1], has been used as a treatment for patients with hereditary orotic aciduria for more than four decades. The therapeutic potential of uridine has been assessed in a diverse group of clinical disorders including cystic fibrosis, liver dysfunction, chemotherapy toxicity, pervasive developmental delay, schizophrenia, epilepsy, and diabetes-induced peripheral neuropathy [2]; and, recently, as a treatment for mitochondrial dysfunction associated with treatment with nucleoside reverse transcriptase inhibitors in patients with HIV infection [3,4,5,6]. Uridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. A food supplement containing nucleosides, NucleomaxXH, has been reported to raise plasma uridine to supraphysiologic levels

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Results

Conclusion