175that are characteristic of the individual can be used to diagnose diseases, predict an
individual’s future illnesses, and their responses to treatments.
The principle of pharmacometabonomics has been demonstrated in humans by
showing a clear connection between an individual’s metabolic phenotype, in the
form of a predose urinary metabolite profi le, and the metabolic fate of a standard
dose of the widely used analgesic acetaminophen (Clayton et al. 2009 ). Predose and
postdose urinary metabolite profi les were determined by^1 H NMR spectroscopy.
The predose spectra were statistically analyzed in relation to drug metabolite excre-
tion to detect predose biomarkers of drug fate and a human-gut microbiome come-
tabolite predictor was identifi ed. Thus, the investigators found that individuals
having high predose urinary levels of p-cresol sulfate had low postdose urinary
ratios of acetaminophen sulfate to acetaminophen glucuronide. They conclude that,
in individuals with high bacterially mediated p-cresol generation, competitive
O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acet-
aminophen. Given that acetaminophen is such a widely used and seemingly well-
understood drug, this fi nding provides a clear demonstration of the immense
potential and power of the pharmacometabonomic approach. However, many other
sulfonation reactions are expected to be similarly affected by competition with
p-cresol and these fi nding also has important implications for certain diseases as
well as for the variable responses induced by many different drugs and xenobiotics.
It is proposed that assessing the effects of microbiome activity should be an integral
part of pharmaceutical development and of personalized health care. Furthermore,
gut bacterial populations might be deliberately manipulated to improve drug effi -
cacy and to reduce adverse drug reactions. Pharmacometabonomics could be used
to preselect volunteers at key stages of the clinical trials. This would enable stratifi -
cation of subjects into cohorts, which could minimize the risk of adverse events, or
focus on those individuals with a characteristic disease phenotype for assessment of
effi cacy.
Metabonomic Technologies for Toxicology Studies
Metabonomics studies demonstrate its potential impact in the drug discovery pro-
cess by enabling the incorporation of safety endpoints much earlier in the drug
discovery process, reducing the likelihood (and cost) of later stage attrition.
Global metabolic profi ling (metabonomics/metabolomics) has shown particular
promise in the area of toxicology and drug development. A metabolic profi le need
not be a comprehensive survey of composition, nor need it be completely resolved
and assigned, although these are all desirable attributes. For the profi le to be useful
across a range of problems, however, it must be amenable to quantitative interpreta-
tion and it should be relatively unbiased in its scope. In addition to explicit quanti-
fi cation of individual metabolites, analytical profi les such as NMR spectra are
effectively functions of the concentrations of the constituents of the sample and
hence can be handled directly as metabolic profi les. A further requirement for the
Metabonomic Technologies for Toxicology Studies