Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans.
Achieving the ability to identify individuals who are susceptible to drug-induced liver injury (DILI) would represent a major advance in personalized medicine. Clayton et al. demonstrated that the pattern of endogenous metabolites in urine could predict susceptibility to acetaminophen-induced liver injury in rats. We designed a clinical study to test this approach in healthy adults who received 4 g of acetaminophen per day for 7 days. Urine metabolite profiles obtained before the start of treatment were not sufficient to distinguish which of the subjects would develop mild liver injury, as indicated by a rise in alanine aminotransferase (ALT) to a level more than twice the baseline value (responders). However, profiles obtained shortly after the start of treatment, but prior to ALT elevation, could distinguish responders from nonresponders. Statistical analyses revealed that predictive metabolites included those derived from the toxic metabolite N-acetyl paraquinone imine (NAPQI), but that the inclusion of endogenous metabolites was required for significant prediction. This "early-intervention pharmaco-metabonomics" approach should now be tested in clinical trials of other potentially hepatotoxic drugs.
Winnike
J H
JH
Department of Biomedical Engineering, University of North Carolina at Chapel Hill, North Carolina, USA.
Li
Z
Z
Wright
F A
FA
Macdonald
J M
JM
O'Connell
T M
TM
Watkins
P B
PB
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008111:Liver Function Tests; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D055815:Young Adult
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000410:Alanine Transaminase