2. Academic Validation
  3. Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells

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

  • J Steroid Biochem Mol Biol. 2019 Apr;188:172-184. doi: 10.1016/j.jsbmb.2018.12.006.
Jere Huovinen 1,  Maija Haj Hussain 2,  Markus Niemelä 2,  Sakari Laaksonen 3,  Hanna-Marja Voipio 3,  Juha Jyrkäs 4,  Janne Mannila 4,  Toni Lassila 4,  Ari Tolonen 4,  Sanna Turunen 2,  Ulrich Bergmann 5,  Petri Lehenkari 6,  Johanna A Huhtakangas 7
Affiliations

Affiliations

  • 1 Cancer 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. Electronic address: [email protected].
  • 2 Cancer 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.
  • 3 Department of Experimental Surgery, Laboratory Animal Centre, Oulu University Hospital and University of Oulu, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland.
  • 4 Admescope, Typpitie 1, 90620, Oulu, Finland.
  • 5 Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 8000, FI-90014, Oulu, Finland.
  • 6 Cancer 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; Division of Operative Care, Oulu University Hospital and University of Oulu, P.O. Box 10, 90029 OYS, Oulu, Finland.
  • 7 Cancer 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; Rheumatology Unit, Department of Medicine, Oulu University Hospital and University of Oulu, MRC, Oulu, P.O. Box 10, 90029 OYS, Finland.
PMID: 30562554 DOI: 10.1016/j.jsbmb.2018.12.006
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.

Keywords

Calcipotriol; Intra-articular dosing; Mesenchymal stromal cell; Metabolism; Pharmacokinetics; Synovial stromal cell.

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