Application of metabonomics in a compound ranking study in early drug development revealing drug-induced excretion of choline into urine.
Selecting drug candidates based on toxicity is an important step in early drug development. In this case study, it is shown how metabonomics is applied to a ranking study, in which drug candidates with equal pharmacological activities are selected based on least toxic side effects. The metabonomic analyses were carried out on an animal study that followed an established protocol for pilot toxicology/ranking studies in rats, however, not specifically modified for a metabonomic assessment. It is shown how conditions not specificially adopted for metabonomics investigations can significantly influence the metabolic profiles recorded by NMR. Furthermore, it is shown how the multivariate analysis of the NMR spectra identified an extreme excretion of an endogenous metabolite into urine induced by two out of the five drug candidates. The subsequent structure elucidation by two-dimensional NMR experiments and a subsequent validation by spiking experiments identified the metabolite as choline. The discussion of the mechanistic background for the excretion of choline, which is usually well-conserved in the body, results in two hypotheses of either a massive degradation of cell membranes or an inhibition of the choline oxidation. Although the validation of these hypotheses needs a follow-up study, the finding of a increased excretion of the important metabolite choline warrants exclusion of these two compounds as viable drug candidates from a metabonomics point of view.
Dieterle
Frank
F
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, PRBD-E, Building 065/512, 4070-Basel, Switzerland.
Schlotterbeck
Götz
G
Ross
Alfred
A
Niederhauser
Urs
U
Senn
Hans
H
D000818:Animals; D002794:Choline / Q000652:urine*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D002794:Choline