NMR-based urine analysis in rats: prediction of proximal tubule kidney toxicity and phospholipidosis.
BACKGROUND
The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach.


METHODS
Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set.


RESULTS
Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG.


CONCLUSIONS
NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.
Lienemann
Kai
K
Intelligent Systems Group, Dortmund University of Technology, Otto-Hahn-Strasse 8, D-44221 Dortmund, Germany.
Plötz
Thomas
T
Pestel
Sabine
S
D000818:Animals; D004333:Drug Administration Routes; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D023421:Models, Animal; D015999:Multivariate Analysis; D004364:Pharmaceutical Preparations / Q000652:urine; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
D004364:Pharmaceutical Preparations; D010743:Phospholipids