Quantitative Assessment of Drug Delivery to Tissues
and Association with Phospholipidosis: A Case Study with Two Structurally
Related Diamines in Development
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 <i>in
vitro</i> and <i>in vivo</i>. 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 <i>in vivo</i> and could be applied for identification of potential
lysosomotropic compounds in drug development