University of Oulu

Jere Huovinen, Maija Haj Hussain, Markus Niemelä, Sakari Laaksonen, Hanna-Marja Voipio, Juha Jyrkäs, Janne Mannila, Toni Lassila, Ari Tolonen, Sanna Turunen, Ulrich Bergmann, Petri Lehenkari, Johanna A. Huhtakangas, Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells, The Journal of Steroid Biochemistry and Molecular Biology, Volume 188, 2019, Pages 172-184, ISSN 0960-0760, https://doi.org/10.1016/j.jsbmb.2018.12.006

Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells

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Author: Huovinen, Jere1; Hussain, Maija Haj1; Niemelä, Markus1;
Organizations: 1Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland
2Department of Experimental Surgery, Laboratory Animal Centre, Oulu University Hospital and University of Oulu, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland
3Admescope, Typpitie 1, 90620, Oulu, Finland
4Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 8000, FI-90014, Oulu, Finland
5Division of Operative Care, Oulu University Hospital and University of Oulu, P.O. Box 10, 90029 OYS, Oulu, Finland
6Rheumatology Unit, Department of Medicine, Oulu University Hospital and University of Oulu, MRC, Oulu, P.O. Box 10, 90029 OYS, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2019070222624
Language: English
Published: Elsevier, 2019
Publish Date: 2020-04-30
Description:

Abstract

Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.1 mg/kg given to one sheep) and intra-articular dose (0.054 mg/kg, 0.216 mg/kg and 0.560 mg/kg given to three sheep). The terminal half-life of calcipotriol was approximately 1 h after an IV dose. After intra-articular dosing, the systemic absorption was between 1 and 13% during the observed 24 h. Hypercalcemia or other clinical adverse effects did not occur in any animal during the study, and no macroscopic or microscopic alterations were seen in the synovium of the calcipotriol-injected knees compared to the vehicle knees. The in vitro metabolism of calcipotriol was analyzed with LC–MS from human synovial and mesenchymal stromal cell cultures. Both cell types were able to metabolize calcipotriol with MC1080 and MC1046 as the main metabolites. CYP24A1 transcripts were strongly induced by a 48-hour calcipotriol exposure in mesenchymal stromal cells, but not consistently in synovial stromal cells, as determined by RT-qPCR. Calcipotriol proved to be safe after a single intra-articular dose with applied concentrations, and it is metabolized by the cells of the joint. Slow dissolution of calcipotriol crystals in the joint can extend the pharmaceutical impact on the synovium, cartilage and subcortical bone.

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Series: Journal of steroid biochemistry & molecular biology
ISSN: 0960-0760
ISSN-E: 1879-1220
ISSN-L: 0960-0760
Volume: 188
Pages: 172 - 184
DOI: 10.1016/j.jsbmb.2018.12.006
OADOI: https://oadoi.org/10.1016/j.jsbmb.2018.12.006
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This work was supported by Sigrid Juselius Foundation, Finnish Medical Foundation and Northern Ostrobothnia Hospital District.
Copyright information: © 2018 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
  https://creativecommons.org/licenses/by-nc-nd/4.0/