Metabonomic assessment of vasculitis in rats.
The vasculitides are a heterogeneous group of lesions characterized by inflammation and necrosis of the vascular wall and have proven to be a disconcerting dilemma in the development of several classes of therapeutics. Metabonomics is an emerging technology having great potential for rapid noninvasive assessment of toxicity in vivo and providing identification of peripheral surrogate markers of toxicity. Metabonomic evaluation of CI-1018, a selective type 4 phosphodiesterase inhibitor associated with vasculitis in rats, was undertaken. Two experiments were performed in which CI-1018 was administered for up to 4 d to groups of male Wistar rats at doses up to 3000 mg/kg. Urine was collected from all animals pretest and daily for metabonomic analysis. Eleven of 38 CI-1018-treated animals were found to have vascular injury of varying severity at doses = or > 750 mg/kg. Principal component analysis produced a clear pattern separation among 8 of 11 animals with lesions and 36 of 37 animals without lesions in samples collected on d 3 or 4. These data demonstrate that the metabonomics approach has significant potential for developing a noninvasive method for identifying vasculitis in rats. It remains to be seen if urinary analyte patterns identified in this study are reproducible and whether a biomarker pattern for vasculitis can be established.
Robertson
D G
DG
Department of Drug Safety Evaluation, Pfizer Global Research and Development, Ann Arbor, MI 48106-1047, USA. donald.robertson@pfizer.com
Reily
M D
MD
Albassam
M
M
Dethloff
L A
LA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001160:Arterioles / Q000473:pathology; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology; D010363:Pattern Recognition, Automated; D010726:Phosphodiesterase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D014657:Vasculitis / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine
D015415:Biomarkers; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4