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Kidney Cortical Transporter Expression across Species Using Quantitative Proteomics.

Abdul Basit1, Zaher Radi1, Vishal S Vaidya1

  • 1Department of Pharmaceutics, University of Washington, Seattle, Washington (A.B., M.K., B.P.); and Pfizer Worldwide Research Development, Drug Safety Research Development, Cambridge, Massachusetts (Z.R., V.S.V.).

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Species differences in kidney transporter abundance impact drug safety. Preclinical species generally show higher transporter levels than humans, affecting drug clearance predictions and toxicity assessments.

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Area of Science:

  • Pharmacology
  • Nephrology
  • Drug Development

Background:

  • Understanding species-specific kidney transporter expression is crucial for predicting drug pharmacokinetics, interactions, and toxicity.
  • Existing knowledge gaps hinder accurate translation of preclinical drug data to human outcomes, particularly for acute kidney injury.

Purpose of the Study:

  • To quantify and compare the protein abundance of 19 key kidney transporters across five species: human, monkey, dog, rat, and mouse.
  • To identify cross-species and sex-dependent variations in transporter expression relevant to drug development.

Main Methods:

  • Quantitative analysis of protein abundance for 19 membrane transporters in kidney cortex samples from human, monkey, dog, rat, and mouse.
  • Statistical analysis to determine significant differences in expression levels and identify correlations between transporters.

Main Results:

  • Most transporters were more abundant in preclinical species than in humans, with notable exceptions like MDR1, OCT3, and OCTN1.
  • Significant cross-species variability was observed for transporters including MRP4, OCTN2, OAT2, and OCT2.
  • Sex differences in transporter abundance were primarily observed in rodents and dogs.

Conclusions:

  • Kidney transporter abundance varies significantly across species and, in some cases, by sex, necessitating careful consideration during drug development.
  • These data are vital for improving animal-to-human drug clearance scaling and for assessing the potential kidney toxicity of new drug candidates.