Special Issue "Transporter-Mediated Drug Interactions"

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A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (31 May 2011)

Special Issue Editor

Guest Editor
Dr. Constanze Hilgendorf

Innovative Medicines and Early Development, Drug Safety and Metabolism, DMPK, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden
E-Mail
Phone: +46 31 706 53 49
Fax: +46 31 776 37 86
Interests: drug transporters in ADME; in-vitro and in-vivo transporter profiling; drug-drug interactions; drug absorption; intestinal metabolism

Special Issue Information

Dear Colleagues,

Advances in the field of in-vitro tools to accurately describe NME’s interactions with enzymes and transport proteins have led to an improved qualitative understanding of putative interaction points and elimination pathways of the NME. Additionally, more sophisticated in vivo methods (KO or humanized animals) are explored and an increasing number of clinical examples of transporter and transporter/enzyme mediated interactions are reported. Scientific and technological development impacts furthermore on the regulatory views on drug interactions. This special issue highlights advances in in vitro and in vivo studies to mechanistically describe drug-transporter interactions and the complementary modeling approaches to quantitatively predict clinical consequences of such interactions. We invite articles covering all aspects from in-vitro work to modeling and clinical interaction studies.

Dr. Constanze Hilgendorf
Guest Editor

Keywords

  • ABC-transporters
  • SLC-transporters
  • vectorial transport
  • enzyme-transporter interplay
  • inhibition
  • induction
  • pharmacogenomics
  • intestine
  • liver
  • kidney
  • blood-brain-barrier

Published Papers (1 paper)

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Research

Open AccessArticle Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells
Pharmaceutics 2011, 3(4), 782-792; doi:10.3390/pharmaceutics3040782
Received: 22 September 2011 / Revised: 11 October 2011 / Accepted: 20 October 2011 / Published: 27 October 2011
Cited by 3 | PDF Full-text (494 KB) | HTML Full-text | XML Full-text
Abstract
P-glycoprotein (P-gp) is an ATP-dependent transporter localized at the apical membrane of the kidney proximal tubules, which plays a role in the efflux of cationic and amphipathic endogenous waste products and xenobiotics, such as drugs, into urine. Studies in mice deficient in P-gp
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P-glycoprotein (P-gp) is an ATP-dependent transporter localized at the apical membrane of the kidney proximal tubules, which plays a role in the efflux of cationic and amphipathic endogenous waste products and xenobiotics, such as drugs, into urine. Studies in mice deficient in P-gp showed generalized proximal tubular dysfunction similar to the phenotype of patients with cystinosis, an autosomal recessive disorder caused by mutations in the lysosomal cystine transporter cystinosin. Renal disease in cystinosis is characterized by generalized dysfunction of the apical proximal tubular influx transporters (so-called renal Fanconi syndrome) developing during infancy and gradually progressing towards end-stage renal disease before the 10th birthday in the majority of patients that are not treated with the cystine-depleting drug cysteamine. Here, we investigated whether the proximal tubular efflux transporter P-gp is affected in cystinosis and whether this might contribute to the development of renal Fanconi syndrome. We used conditionally immortalized (ci) proximal tubular epithelial cells (ciPTEC) derived from cystinotic patients and healthy volunteers. P-gp-mediated transport was measured by using the P-gp substrate calcein-AM in the presence and absence of the P-gp-inhibitor PSC833. P-gp activity was normal in cystinotic cells as compared to controls. Additionally, the effect of cysteamine on P-gp transport activity and phosphate uptake was determined; demonstrating increased P-gp activity in cystinotic cells, and further decrease of proximal tubular phosphate uptake. This observation is compatible with the persistence of renal Fanconi syndrome in vivo under cysteamine therapy. In summary, P-gp expression and activity are normal in cystinotic ciPTEC, indicating that P-gp dysfunction is not involved in the pathogenesis of cystinosis. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Interactions)

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