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03-03-2011 | Cardiometabolic | Article

NMR-based metabonomics may help assess statin-induced toxicity

Abstract

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MedWire News: The use of nuclear magnetic resonance (NMR)-based metabonomics may be a new and valuable strategy for identifying statin-induced toxicity, Korean researchers suggest.

Statins are widely used but excessive doses can induce toxicity, especially in the muscle and liver. Current biomarkers for toxicity - namely alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine kinase - are typically elevated only in the later stages of tissue damage, so finding alternative markers would be advantageous.

In this study, Sunghyouk Park (Inha University, Incheon, Republic of Korea) and colleagues investigated whether NMR-based metabonomics urine analysis might be useful for assessing statin-induced toxicity.

"NMR-based metabonomic analysis of urine samples offers several advantages in that urine samples can be obtained non-invasively and that they reflect more systemic effects than individual biochemical enzymes," explain the researchers.

"Moreover, NMR spectroscopy can give structural information about the potential biomarkers," they add.

The group obtained urine samples from rats at baseline and after 10 days of treatment with either simvastatin (at a toxic dose of 80 mg/kg of body weight) or control (vehicle). After 10 days the rats were euthanized and blood samples and liver samples taken.

Writing in the open-access journal PLoS One, Park's team reports that AST, ALT, and CK levels were all within the normal range in vehicle-treated animals, whereas AST and ALT, but not CK, were significantly elevated in the statin-treated animals.

They then analyzed NMR spectropscopy data, comparing spectra from urine before and after simvastatin therapy. Multivariate analysis identified three marker metabolites that were significantly elevated by statin therapy and associated with statin-induced toxicity, namely allantoin, 2-oxoglutarate, and trimethylamine-N-oxide.

The impact of statin therapy was further categorized into two subgroups based on the NMR profiles: weak toxicity and high toxicity. These were subsequently validated against findings from blood and liver analysis.

Finally, toxicity at day 10 was strongly associated with metabolic profiles at day 6, with a divergence of toxic effects most notable between the weak and high toxicity subgroups at this time-point, suggesting that the likelihood of statin-induced side effects can be predicted less than a week after starting therapy.

"Taken together, NMR-based metabolite profiling combined with multivariate analysis may provide new criteria for evaluating the simvastatin-induced toxicity that can complement currently available biochemical or histopathological measures," the authors conclude.

"With the convenience of sample collection, the possibility of predicting the future responses, and the technical robustness, this approach is expected to find broader applications in other drug-induced toxicity assessments."

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Joanna Lyford