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Quantitative Assess...
Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
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- Loryan, Irena, 1977- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab
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- Hoppe, E. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Hansen, K. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Held, Felix (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper,Department of Mathematical Sciences,Chalmers tekniska högskola,Chalmers University of Technology,Stiftelsen Fraunhofer-Chalmers Centrum för Industrimatematik (FCC),Fraunhofer-Chalmers Research Centre for Industrial Mathematics (FCC),Fraunhofer Chalmers Ctr, Chalmers Sci Pk, S-41288 Gothenburg, Sweden.; Chalmers Univ Technol, Dept Math Sci, S-41296 Gothenburg, Sweden.; Univ Gothenburg, S-41296 Gothenburg, Sweden
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- Kless, A. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Linz, K. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Marossek, V. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Bayer AG, Wuppertal, Germany
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- Nolte, B. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Peter Greven Physioderm GmbH, Euskirchen, Germany
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- Ratcliffe, P. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Saunders, D. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Terlinden, R. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Wegert, A. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Mercachem, Nijmegen, Netherlands
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- Welbers, A. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Will, O. (författare)
- Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany
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- Hammarlund-Udenaes, Margareta (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab,Translational PKPD
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(creator_code:org_t)
- 2017-11-03
- 2017
- Engelska.
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:12, s. 4362-4373
- Relaterad länk:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://research.cha...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- drug induced phospholipidosis
- unbound drug
- intracellular concentration
- brain slice
- lung slice
- brain-slice method
- high-throughput
- polar lipids
- cell
- alveolar
- barrier
- binding
- cns
- microdialysis
- hepatocytes
- Research & Experimental Medicine
- Pharmacology & Pharmacy
- cns
- Farmaceutisk farmakologi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Loryan, Irena, 1 ...
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Hoppe, E.
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Hansen, K.
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Held, Felix
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Kless, A.
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Linz, K.
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visa fler...
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Marossek, V.
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Nolte, B.
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Ratcliffe, P.
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Saunders, D.
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Terlinden, R.
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Wegert, A.
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Welbers, A.
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Will, O.
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Hammarlund-Udena ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Farmaceutiska ve ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Farmakologi och ...
- Artiklar i publikationen
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Molecular Pharma ...
- Av lärosätet
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Göteborgs universitet
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Chalmers tekniska högskola
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Uppsala universitet