Application of metabonomics in a comparative profiling study reveals N-acetylfelinine excretion as a biomarker for inhibition of the farnesyl pathway by bisphosphonates.
In this work, the results of metabolic profiling of urine from a preclinical comparative profiling study with the two biphosphonates ibandronate and zoledronate are reported. Toxicological assessment showed very different effects for the two compounds. Ibandronate did not cause major signs of toxicity, whereas zoledronate elicited hepatotoxicity and nephrotoxicity. Increased levels of urinary glucose and decreased levels of urinary creatinine detected by NMR also indicated drug-induced nephrotoxicity. Similarly, increased urinary levels of creatine and taurine indicated hepatotoxicity. Both organ toxicities were later confirmed by histopathology. In addition, the benefit of metabonomics as an open approach as compared to targeted methods was demonstrated by the identification of an unknown molecule in the urine of rats dosed with zoledronate. The structure elucidation revealed this molecule as N-acetylfelinine. Analysis of the pathways proposed for the biochemical synthesis of this molecule showed that the synthesis and excretion of N-acetylfelinine could easily be explained by drug-induced inhibition of farnesyl diphosphate synthase. This is the reported mode of action of bisphosphonates. Until now, N-acetylfelinine was exclusively observed in the urine of felidae species, where it is believed to be a precursor to a pheromone.
Dieterle
Frank
F
Pharmaceuticals Division, F. Hoffman-La Roche Ltd., 4070 Basel, Switzerland.
Schlotterbeck
Götz
G
Binder
Martin
M
Ross
Alfred
A
Suter
Laura
L
Senn
Hans
H
D000818:Animals; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D003401:Creatine / Q000652:urine; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000652:urine; D004164:Diphosphonates / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000032:analysis; D000077557:Ibandronic Acid; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity; D015394:Molecular Structure; D054876:Prenylation / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction; D013654:Taurine / Q000652:urine; D000077211:Zoledronic Acid
D015415:Biomarkers; D004164:Diphosphonates; D007093:Imidazoles; D013654:Taurine; D000077211:Zoledronic Acid; C098250:felinine; D051228:Geranyltranstransferase; D005947:Glucose; D003545:Cysteine; D003401:Creatine; D000077557:Ibandronic Acid