Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
Artikel i vetenskaplig tidskrift, 2017

Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.





brain-slice method


polar lipids





Irena Loryan

Uppsala universitet

Edmund Hoppe

Grunenthal GmbH

Klaus Hansen

Grunenthal GmbH

Felix Held

Chalmers, Matematiska vetenskaper, Analys och sannolikhetsteori

Göteborgs universitet

Achim Kless

Grunenthal GmbH

Klaus Linz

Grunenthal GmbH

Virginia Marossek

Grunenthal GmbH

Bert Nolte

Grunenthal GmbH

Paul Ratcliffe

Grunenthal GmbH

Derek Saunders

Grunenthal GmbH

Rolf Terlinden

Grunenthal GmbH

Anita Wegert

Grunenthal GmbH

Andre Welbers

Grunenthal GmbH

Olaf Will

Grunenthal GmbH

Margareta Hammarlund-Udenaes

Uppsala universitet

Molecular Pharmaceutics

1543-8384 (ISSN) 1543-8392 (eISSN)

Vol. 14 4362-4373


Farmakologi och toxikologi