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INTRODUCTION

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Uridine triacetate (2′,3′,5′-tri-O-acetyluridine) is used to treat cases of ­toxicity from fluoropyrimidines such as fluorouracil and fluorouracil prodrugs such as capecitabine and tegafur. Uridine triacetate is a prodrug that is taken orally to provide uridine as a source for uridine triphosphate for endogenous RNA incorporation.

HISTORY

In 1950, leucovorin (folinic acid) successfully mitigated chemotherapeutic toxicity from aminopterin and methotrexate, for which folate antidotal therapy was inefficacious.39 Fluorouracil (5-FU) synthesis and its antitumor activity were reported in 1957.18 A decade later, the concept of leucovorin “rescue” emerged to mitigate toxicity from higher methotrexate chemotherapy doses.27 However, in 1982 leucovorin was reported to paradoxically both increase 5-FU chemotherapeutic efficacy as well as cytotoxicity in humans by increasing inhibition of thymidylate synthase.30 Additional ­studies in 1982 reported successful use of uridine to “rescue” mice from lethal 5-FU doses, as well as the ability to deliver higher 5-FU chemotherapeutic doses with concomitant uridine.25,32 Human phase 1 uridine rescue trials soon followed in 1984.28 Intravenous uridine was associated with severe phlebitis when administered peripherally and with cellulitis and thrombosis when given centrally.41,42 This necessitated a shift toward oral administration. However, oral uridine was limited by poor bioavailability.43 To prevent uridine catabolism by uridine phosphorylase and increase lipophilicity, uridine was modified to uridine triacetate in the late 1980s45 and introduced in mice in 1996.4 Phase 1 human studies of oral uridine, then also known as PN401, were reported soon after in 1997.22 Meanwhile, capecitabine, which was synthesized in the early 1990s and patented abroad in 1992, underwent pilot/phase 1 studies in 1996 and received US market approval in 1998.3,5,17 The FDA designated uridine triacetate an orphan product in 2009, and ultimately granted marketing approval in January 2015 to treat 5-FU or capecitabine overdose and early-onset, severe or life-threatening toxicity.6

PHARMACOLOGY

Chemistry/Preparation

Uracil (demethylated thymine) is a naturally occurring pyrimidine and one of the 4 fundamental bases of ribonucleic acid (RNA). Uracil has a molecular weight of 112.1 Da. Uridine is uracil attached by a β-N1-glycosidic bond to a ribose ring. Uridine triacetate (or triacetyluridine) is uridine that has been triacetylated at the 2′,3′, and 5′ positions. Uridine triacetate has a molecular weight of 370.3 Da.

Mechanism of Action

Uridine as uridine triphosphate is an essential component of RNA, while uridine as uridine diphosphate glucose is an important precursor to glycogen synthesis.48 Mechanisms of toxicity by the fluoropyrimidines (5-FU, capecitabine, tegafur, and floxuridine) are reviewed in Chap. 51 and summarized in Fig. 51–2. The 5-FU metabolite fluorouridine triphosphate (FUTP) is incorporated in RNA. Uridine triacetate, once absorbed and metabolized, supplies uridine, which can serve as a source for uridine triphosphate to compete with ...

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