title: Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro.
abstract: OBJECTIVE
  Islet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets.
  
  
  METHODS
  We determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48 h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR.
  
  
  RESULTS
  Islets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR-signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus.
  
  
  CONCLUSIONS
  These findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets.
authors.affiliation: Department of Transplantation Medicine, Oslo University Hospital, Norway.|Institute for Surgical Research, University of Oslo, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Kloster-Jensen
authors.affiliation: Department of Pharmacology, Oslo University Hospital, Norway.
authors.forename: Nils Tore
authors.initials: NT
authors.lastname: Vethe
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Norway.
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.affiliation: Department of Transplantation Medicine, Oslo University Hospital, Norway.|Institute for Surgical Research, University of Oslo, Norway.
authors.forename: Shadab
authors.initials: S
authors.lastname: Abadpour
authors.affiliation: Department of Immunology Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.affiliation: Department of Transplantation Medicine, Oslo University Hospital, Norway.|Institute for Surgical Research, University of Oslo, Norway.|Faculty of Medicine, University of Oslo, Norway.
authors.forename: Aksel
authors.initials: A
authors.lastname: Foss
authors.affiliation: Department of Pharmacology, Oslo University Hospital, Norway.|School of Pharmacy, University of Oslo, Norway.
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
authors.affiliation: Department of Transplantation Medicine, Oslo University Hospital, Norway.|Institute for Surgical Research, University of Oslo, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Scholz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000328:Adult; D000368:Aged; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism; D009994:Osmolar Concentration; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus; D016559:Tacrolimus
keywords: diabetes; human islets; immunosuppressive drugs; intracellular drug concentration; sirolimus; tacrolimus