Cited by 31Pharmacogenetics and Drug MetabolismComputational Drug Discovery MethodsPharmaceutical studies and practices

Tissue lipids and drug distribution: Dog versus rat

Rodgers, Trudy, Jones, Hannah M., Rowland, Malcolm·2012·Journal of Pharmaceutical Sciences

Abstract

A key parameter in whole-body physiologically based pharmacokinetic models is the tissue-to-plasma water partition coefficient (K(pu)), which is commonly assumed consistent across all species for all tissues for passively distributing drugs. Many drugs primarily bind to tissue lipids and although considerable tissue lipid concentration data exist in rodents, data on these and K(pu) values in larger animals and humans are sparse to negligible. To test the above assumption, lipid levels were quantified in 13 dog tissues, then compared with the values in rat, and used to predict and compare K(pu) values between these species. For many tissues, including muscle, lipid concentrations were comparable in dog and rat. However, spleen acidic phospholipid levels were sevenfold lower, skin neutral phospholipid threefold lower, and neutral lipids fivefold, 12-fold, and eightfold lower in brain, lung, and spleen, respectively, and fourfold higher in bone in dog than in rat. Such differences resulted in significant predicted K(pu) differences. In contrast, unbound volume of distribution (Vu(ss)), a global measure of distribution, showed generally good agreement (predictions and observations) between dog and rat for a diverse compound set, indicating tissues with large-predicted K(pu) species differences tend either to contribute to Vu(ss) to a limited extent, and/or occur in opposing directions tending to cancel each other out.

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Crossref · 10.1002/jps.23285

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Authors
Rodgers, T., Jones, H. M., & Rowland, M.
Affiliations
  • University of Manchester (GB)
  • Pfizer (United States) (US)
Corresponding author
Rodgers, Trudy
Venue
Journal of Pharmaceutical Sciences
Publisher
Elsevier BV
Published
2012-12
Volume
101
Issue
12
Pages
4615-4626
ISSN
0022-3549 (ISSN-L)
OpenAlex
W2029267669
Cited by
31
References
48
Citations by year
2026: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 6 · 2012: 1
FWCI
4.34
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Pharmaceutical Sciences (publishedVersion)
  • PubMed (publishedVersion)
Funders
University of Manchester
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords
tissue lipids, drug distribution, tissue-to-plasma partition coefficient, species differences, dogs, rats, physiologically based pharmacokinetic modeling, phospholipids
MeSH terms
Animals, Computer Simulation, Dogs, Lipids, Male, Models, Biological, Pharmacokinetics, Tissue Distribution, Rats, Sprague-Dawley, Rats

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