9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 19-21 July 2007, Sydney, Australia

SINGLE-DOSE AND CUMULATIVE PHARMACOKINETICS OF THE FOOD SUPPLEMENT NUCLEOMAXX® AND MECHANISM FOR ENHANCED BIOAVAILABILITY OF URIDINE

Antiviral Therapy 2007; 12(Suppl. 2):Lx (abstract no. P-06)

ME Weinberg¹, MC Roman², P Jacob¹, M Wen¹, L Yu¹, UA Walker³, K Mulligan¹ and M Schambelan^1
1University of California San Francisco, San Francisco, CA, USA; ²Tampa Bay Analytical Research Inc., Largo, FL, USA; ³Medizinische Universitatsklinik, Freiburg, Germany

OBJECTIVES: Uridine supplementation is being investigated as a novel therapy for mitochondrial dysfunction. Administration of NucleomaxX®, a food supplement derived from sugar cane, achieves higher peak uridine levels than those reported in studies using similar doses of pure uridine. We performed single- and multiple-dose pharmacokinetic (PK) studies to determine whether repeated dosing with NucleomaxX® results in augmented plasma uridine levels, as well as product analysis to explore its enhanced bioavailability.

METHODS: Eight healthy volunteers (four men and four women) were hospitalized on a metabolic ward for 7 days and fed a constant diet. One sachet (36 g) of NucleomaxX® mixed with 300 ml of liquid was administered as a single dose on Day 1. Subjects were then dosed every 8 h during days 2–6 and once on day 7. Twenty-four-hour PK parameters were compared between days 1 and 7 by paired t-tests. For the product analysis, nucleosides were extracted in aqueous solution containing ascorbic acid and quantified by reversed-phase HPLC with UV detection.

RESULTS: In the men, plasma uridine levels at 0800 h were 4.8 ±0.5 µM and 33.4 ±4.2 µM (P=0.0008), rising to maximal concentrations of 128.1 ±25.4 µM and 162.7± 21.2 µM (P=0.07) 1–2 h after dosing on days 1 and 7, respectively. Mean plasma uridine levels (95.4 ±60.3 versus 70.4 ±53.3 µM, P=0.0001) and AUCs (1,429 ±247 versus 1,045 ±208 µM/h, P=0.013) were higher on day 7 than on day 1, indicating a cumulative effect after repeated dosing. Product analysis revealed that each sachet of NucleomaxX® contains 1.61% (0.6 g) uridine and 15.0% (5.4 g) 2′,3′,5′-tri-O-acetyluridine (TAU), which is converted to uridine by plasma esterases. Previous studies have shown that, compared with pure uridine, TAU exhibits enhanced gastrointestinal tract absorption and is resistant to catabolism by uridine phosphorylase.

CONCLUSIONS: Repeated dosing with NucleomaxX® resulted in a mean peak plasma uridine concentration >150 µM, a level far greater than that reported with equimolar amounts of pure uridine and in a range known to ameliorate mitochondrial toxicity in vitro. The increased bioavailability may be due to the high proportion (>90%) of TAU in the nucleoside component of NucleomaxX®.

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2007-07-24
P-06

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