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  • Loryan, Irena,1977-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab (författare)

Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development

  • Artikel/kapitelEngelska2017

Förlag, utgivningsår, omfång ...

  • 2017-11-03
  • American Chemical Society (ACS),2017

Nummerbeteckningar

  • LIBRIS-ID:oai:gup.ub.gu.se/262617
  • https://gup.ub.gu.se/publication/262617URI
  • https://doi.org/10.1021/acs.molpharmaceut.7b00480DOI
  • https://research.chalmers.se/publication/254130URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-342077URI

Kompletterande språkuppgifter

  • Språk:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Hoppe, E.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Hansen, K.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Held, FelixGothenburg 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(Swepub:cth)hefelix (författare)
  • Kless, A.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Linz, K.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Marossek, V.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Bayer AG, Wuppertal, Germany (författare)
  • Nolte, B.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Peter Greven Physioderm GmbH, Euskirchen, Germany (författare)
  • Ratcliffe, P.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Saunders, D.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Terlinden, R.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Wegert, A.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany.; Mercachem, Nijmegen, Netherlands (författare)
  • Welbers, A.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Will, O.Grünenthal GmbH,Grunenthal GmbH, D-52099 Aachen, Germany (författare)
  • Hammarlund-Udenaes, MargaretaUppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab,Translational PKPD(Swepub:uu)marghamm (författare)
  • Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Molecular Pharmaceutics: American Chemical Society (ACS)14:12, s. 4362-43731543-83841543-8392

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