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Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets invitro
Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway..
Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway..
Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway..
Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway..
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2015 (English)In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 28, no 10, 1152-1161 p.Article in journal (Refereed) Published
Abstract [en]

Main problemIslet 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. MethodsWe 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 48h. 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. ResultsIslets 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. ConclusionThese 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.

Place, publisher, year, edition, pages
2015. Vol. 28, no 10, 1152-1161 p.
Keyword [en]
diabetes, human islets, immunosuppressive drugs, intracellular drug concentration, sirolimus, tacrolimus
National Category
Endocrinology and Diabetes Immunology in the medical area
URN: urn:nbn:se:uu:diva-263426DOI: 10.1111/tri.12617ISI: 000360758500004PubMedID: 26046470OAI: oai:DiVA.org:uu-263426DiVA: diva2:860615
Available from: 2015-10-13 Created: 2015-09-30 Last updated: 2015-10-13Bibliographically approved

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Korsgren, Olle
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Clinical ImmunologyScience for Life Laboratory, SciLifeLab
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