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Use of Rabbit Eyes in Pharmacokinetic Studies of Intraocular Drugs
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Use of Rabbit Eyes in Pharmacokinetic Studies of Intraocular Drugs

Published on: July 23, 2016

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In vitro ocular metabolism and bioactivation of ketoconazole in rat, rabbit and human

Amanda L Cirello1, Jennifer L Dumouchel1, Mithat Gunduz1

  • 1Novartis Institutes for BioMedical Research, Analytical Sciences and Imaging, Cambridge, MA 02139, USA.

Drug Metabolism and Pharmacokinetics
|February 1, 2017
PubMed

Insights

This study investigated ketoconazole metabolism in ocular tissues. Researchers identified eight human ocular metabolites, revealing new insights into ocular drug metabolism and bioactivation pathways.

Area of Science:

  • Ophthalmology
  • Pharmacology
  • Drug Metabolism

Background:

  • Oral ketoconazole treats severe fungal keratitis.
  • Ocular metabolism of ketoconazole is poorly understood.
  • Understanding ocular metabolism is vital for drug development and risk assessment.

Purpose of the Study:

  • Investigate ketoconazole metabolism in rat, rabbit, and human ocular S9 fractions.
  • Compare ocular metabolism with liver metabolism.
  • Identify ocular metabolites and metabolic pathways.

Main Methods:

  • In vitro incubation of ketoconazole with ocular and liver S9 fractions from rats, rabbits, and humans.
  • Identification of metabolites using analytical techniques.
  • Trapping studies to confirm reactive intermediates.

Main Results:

  • Eleven putative ketoconazole metabolites were identified in vitro.
  • Six metabolites were found in rat ocular S9 fractions.
  • Eight metabolites were identified in rabbit and human ocular S9 fractions.
  • Metabolic pathways suggested reactive intermediate formation in rabbit and human ocular and liver S9 fractions.
  • Eight human ocular metabolites of ketoconazole were identified for the first time.

Conclusions:

  • This study provides the first report on ocular metabolic pathways and bioactivation of ketoconazole in preclinical species and humans.
  • Identified human ocular metabolites and pathways are crucial for future ocular therapeutic development.
  • Findings contribute to risk assessment for ketoconazole and related drugs in ocular treatments.
Keywords:
BioactivationLiver S9 fractionsOcular S9 fractionsOcular metabolismPotassium cyanide

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