Tissue lipids and drug distribution: Dog versus rat

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.