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.

high-throughput

binding

hepatocytes

polar lipids

brain-slice method

microdialysis

alveolar

cns

barrier

cell

Författare

[Person ca275341-b48b-4a1c-9323-9d05fbd2ed82 not found]

Uppsala universitet

[Person a2261de3-6b7e-42fb-9de4-80741ee72518 not found]

Grünenthal GmbH

[Person 490f0f13-2e7e-49cc-b429-e8776d4a9097 not found]

Grünenthal GmbH

[Person 1eae7fc3-fcd3-4a3f-b29c-8c98485fd1cd not found]

Chalmers, Matematiska vetenskaper, Analys och sannolikhetsteori

Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik

[Person ad959662-4f4b-449c-be75-17196ab4e08b not found]

Grünenthal GmbH

[Person cb67a36e-6a12-42d0-9517-ef24d49f1277 not found]

Grünenthal GmbH

[Person 62307b31-f956-4bc7-bdef-d84cdedbbd69 not found]

Grünenthal GmbH

[Person f05c18b3-1c46-4604-83b7-bf436b1fd3f1 not found]

Grünenthal GmbH

[Person ef746388-5ec4-420f-9cfd-55e5d6c157b4 not found]

Grünenthal GmbH

[Person f8827b9e-9157-4a1e-b824-314b55657e6d not found]

Grünenthal GmbH

[Person 2b844a21-6d1d-4def-8a42-7bdb6fd3fc7f not found]

Grünenthal GmbH

[Person cdaed6a5-b0ef-4543-af96-9cde453b5826 not found]

Grünenthal GmbH

[Person 4649fe3b-5c27-4a6c-8ce1-d8c178b13a71 not found]

Grünenthal GmbH

[Person 32f14a5d-afb0-4bbf-8ad3-0887df1c5aa3 not found]

Grünenthal GmbH

[Person e2af3e84-12ba-4761-a783-a3d7fa8ccec8 not found]

Uppsala universitet

Molecular Pharmaceutics

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

Vol. 14 12 4362-4373

Ämneskategorier

Farmakologi och toxikologi

DOI

10.1021/acs.molpharmaceut.7b00480

PubMed

29099189

Mer information

Senast uppdaterat

2018-08-24