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Development of PBPK model of molinate and molinate sulfoxide in rats and humans

Andrew Campbell1

  • 1Department of Environmental Toxicology, UC Davis, Davis, CA 95616, USA. arc40@astound.net

Regulatory Toxicology and Pharmacology : RTP
|June 24, 2009
PubMed

Insights

This study developed a physiologically-based pharmacokinetic (PBPK) model to assess testicular toxicity risk from the herbicide molinate. The model, validated in rats, was extrapolated to humans, predicting molinate concentrations in blood and testes.

Area of Science:

  • Environmental toxicology
  • Pharmacokinetics
  • Reproductive toxicology

Background:

  • Molinate is a widely used herbicide in California rice fields.
  • Molinate sulfoxide, a metabolite, is suspected of causing testicular toxicity in rats.
  • Humans produce similar molinate metabolites as rats.

Purpose of the Study:

  • To develop a preliminary physiologically-based pharmacokinetic (PBPK) model for molinate.
  • To validate the PBPK model in rats.
  • To extrapolate the model to humans for reproductive risk assessment.

Main Methods:

  • A seven-compartment PBPK model was constructed for male Sprague-Dawley rats.
  • The model incorporated flow-limited and diffusion-limited rate equations.
  • Model simulations were compared against experimental molinate concentrations from oral and intravenous doses in rats and a human oral dose.

Main Results:

  • The PBPK model accurately predicted molinate blood concentrations in rats across various doses.
  • The model successfully predicted human molinate blood concentrations after a 5.06mg oral dose.
  • Sensitivity analysis identified key parameters influencing molinate and molinate sulfoxide concentrations.

Conclusions:

  • The PBPK model provides a valuable tool for assessing molinate's reproductive risk.
  • Extrapolation to humans suggests potential for molinate exposure assessment.
  • Key factors influencing testicular exposure to molinate sulfoxide were identified.

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