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Amoxapine Demonstrates Incomplete Inhibition of β-Glucuronidase Activity from Human Gut Microbiota

Wei Yang1, Bin Wei1, Ru Yan1,2

  • 11 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.

SLAS Discovery : Advancing Life Sciences R & D
|August 16, 2017
PubMed

Insights

Amoxapine poorly inhibits human gut microbiota beta-glucuronidase, explaining its limited efficacy against CPT-11 toxicity. Drug screening requires human gut microbiota models for accurate predictions.

Area of Science:

  • Pharmacology
  • Microbiology
  • Drug Discovery

Background:

  • Amoxapine is a potent inhibitor of Escherichia coli beta-glucuronidase.
  • CPT-11 (Irinotecan) induces gastrointestinal toxicity, partly mediated by beta-glucuronidase activity.
  • The efficacy of amoxapine in mitigating this toxicity is variable and not fully understood.

Purpose of the Study:

  • To investigate the factors contributing to amoxapine's unsatisfactory efficacy in alleviating CPT-11-induced gastrointestinal toxicity.
  • To evaluate amoxapine's inhibitory effects on beta-glucuronidase activity in human gut microbiota.
  • To predict the clinical outcomes of amoxapine's beta-glucuronidase inhibition in humans.

Main Methods:

  • Assessed amoxapine's inhibition of beta-glucuronidase from pooled and individual human gut microbiota.
  • Determined kinetic parameters (Km, Vmax) using Michaelis-Menten kinetics.
  • Tested amoxapine's inhibitory effects on beta-glucuronidases from 13 different bacterial isolates.
  • Evaluated amoxapine's impact on gut microbiota growth at high concentrations.

Main Results:

  • Amoxapine showed potent inhibition of E. coli beta-glucuronidase (IC50 = 0.34 µM) but poor and varied inhibition of human gut microbiota beta-glucuronidase (IC50 >100 µM).
  • Human gut microbiota exhibited similar substrate affinity (Km) but diverse catalytic capabilities (Vmax).
  • Amoxapine displayed variable inhibitory effects (8.7%-100%) across different bacterial isolates and inhibited microbiota growth at 200 µM.

Conclusions:

  • Amoxapine's poor inhibition of human gut microbiota beta-glucuronidase partly explains its limited efficacy against CPT-11-induced toxicity.
  • These findings predict a poor outcome for beta-glucuronidase inhibition therapy using amoxapine in humans.
  • Drug screening for CPT-11 toxicity mitigation necessitates the use of human gut microbiota models.
Keywords:
CPT-11–induced toxicityamoxapinebacterial isolateshuman gut microbiotaβ-glucuronidase inhibition

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