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Metabolomic screening and identification of the bioactivation pathways of ritonavir

Feng Li1, Jie Lu, Xiaochao Ma

  • 1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.

Chemical Research in Toxicology
|November 2, 2011
PubMed

Insights

Ritonavir (RTV) causes side effects through unknown metabolic pathways. This study identified novel RTV metabolites and proposed five bioactivation pathways, with CYP3A involvement confirmed in mice and human liver microsomes.

Area of Science:

  • Pharmacology
  • Metabolomics
  • Toxicology

Background:

  • Ritonavir-boosted protease inhibitors are crucial for HIV treatment.
  • The mechanisms underlying ritonavir's toxicity remain unclear.
  • Understanding ritonavir metabolism is key to mitigating its side effects.

Purpose of the Study:

  • To investigate the metabolic pathways of ritonavir.
  • To identify novel ritonavir metabolites.
  • To explore potential bioactivation pathways linked to ritonavir toxicity.

Main Methods:

  • Metabolomic analysis in mice to identify ritonavir metabolites.
  • Structural elucidation of novel metabolites.
  • Involvement of Cytochrome P450 3A (CYP3A) assessed using Cyp3a-null mice.
  • Recapitulation of pathways in human liver microsomes.

Main Results:

  • Identified 26 ritonavir metabolites in mice, with 13 being novel.
  • Novel metabolites include glycine and N-acetylcysteine conjugates, and ring-open products.
  • Proposed five potential bioactivation pathways involving sulfation and epoxidation.
  • Confirmed CYP3A involvement in four bioactivation pathways.
  • All five pathways were observed in human liver microsomes.

Conclusions:

  • Novel ritonavir metabolites and bioactivation pathways have been identified.
  • CYP3A plays a significant role in ritonavir bioactivation.
  • These findings provide insights into ritonavir-induced toxicity.
  • Further research is warranted to elucidate the precise role of CYP3A and these pathways in ritonavir toxicity.

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