Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells
| Autor: | Ulrich Bergmann, Ari Tolonen, Markus Niemelä, Janne Mannila, Hanna-Marja Voipio, Sanna Turunen, Sakari Laaksonen, Maija Haj Hussain, Jere Huovinen, Petri Lehenkari, Toni Lassila, Johanna A. Huhtakangas, Juha Jyrkäs |
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| Rok vydání: | 2018 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Male Cell type Stromal cell Endocrinology Diabetes and Metabolism Clinical Biochemistry Anti-Inflammatory Agents Arthritis Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology CYP24A1 Pharmacokinetics Calcitriol medicine Animals Humans Calcipotriol Molecular Biology Cells Cultured Sheep Cartilage Mesenchymal stem cell Synovial Membrane Mesenchymal Stem Cells Cell Biology medicine.disease 030104 developmental biology medicine.anatomical_structure intra-articular dosing chemistry synovial stromal cell 030220 oncology & carcinogenesis mesenchymal stromal cell Molecular Medicine Female metabolism pharmacokinetics |
| Zdroj: | The Journal of steroid biochemistry and molecular biology. 188 |
| ISSN: | 1879-1220 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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