Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism.
We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by (1)H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.
Clayton
T Andrew
TA
SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, United Kingdom.
Baker
David
D
Lindon
John C
JC
Everett
Jeremy R
JR
Nicholson
Jeremy K
JK
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D001419:Bacteria / Q000254:growth & development / Q000378:metabolism*; D003408:Cresols / Q000378:metabolism* / Q000652:urine; D041981:Gastrointestinal Tract / Q000378:metabolism* / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D013431:Sulfates / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000378:metabolism / Q000652:urine; D055815:Young Adult
D018712:Analgesics, Non-Narcotic; D003408:Cresols; D013431:Sulfates; D013463:Sulfuric Acid Esters; C032538:4-cresol; D000082:Acetaminophen; C408690:4-cresol sulfate; C037386:acetaminophen glucuronide