title: Magnesium-deficiency does not alter calcineurin inhibitors activity in mice.
abstract: BACKGROUND
  Tacrolimus (TAC) and cyclosporin (CsA) are commonly responsible for hypomagnesemia that predisposes in turn for hypertension, renal impairment and encephalopathy.
  
  
  OBJECTIVE
  The effects of TAC on Mg(2+)-homeostasis and of pre-existing Mg(2+)-deficiency on TAC immunosuppressive activity were compared to CsA in mice.
  
  
  METHODS
  Mg(2+) was quantified in plasma, erythrocytes, urine, feces, and femurs from mice treated with TAC 5mg/kg/day. Immunosuppression was assessed in splenocytes by mixed lymphocyte reaction, IL-2 quantification and CN activity determination.
  
  
  RESULTS
  Plasma and urine Mg(2+) levels in TAC-treated mice were significantly lower from day 7 until day 21 (p<0.05 versus control) and returned to control value at day 28. Mg(2+) levels were unchanged in erythrocyte, feces and femur. Inhibition of allogeneic proliferation, IL-2 production and CN activity were 68, 56 and 30% lower (p<0.01) after 7 days of TAC-treatment, and 72, 68 and 51% lower (p<0.01) after 7 days of CsA-treatment with a dose of 50mg/kg/day. Dietary-induced hypomagnesemia resulted in significant inhibition of CN activity (p<0.01) without alteration of IL-2 production or allogeneic proliferation. However, it did not alter the effects observed with CsA- or TAC-treatment on allogeneic proliferation, IL-2 production and CN activity.
  
  
  CONCLUSIONS
  By contrast with CsA, long-course TAC-treatment induced an early, but transient, and moderate hypomagnesemia without alteration of bone or erythrocyte stocks, intestinal absorption or renal function. Therefore, in clinical use, TAC should be preferred to CsA in patients with pathological or pharmacological conditions which favor Mg(2+)-deficiency. However, dietary-induced hypomagnesemia did not alter the immunosuppressive effects of TAC and CsA.
authors.affiliation: Department of Pharmacology, AP-HP, CHU H. Mondor, 94010 Créteil, France. anne.hulin@hmn.aphp.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Hulin
authors.forename: Lilia
authors.initials: L
authors.lastname: Lamrani
authors.forename: Fadi
authors.initials: F
authors.lastname: Sabbagh
authors.forename: Anne
authors.initials: A
authors.lastname: Tallet
authors.forename: Florence
authors.initials: F
authors.lastname: Lecerf
authors.forename: Pierre
authors.initials: P
authors.lastname: Bac
authors.forename: Michèle
authors.initials: M
authors.lastname: German-Fattal
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D019587:Dietary Supplements; D004912:Erythrocytes / Q000737:chemistry; D005243:Feces / Q000737:chemistry; D005260:Female; D005269:Femur / Q000737:chemistry; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007376:Interleukin-2 / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008274:Magnesium / Q000097:blood / Q000652:urine; D008275:Magnesium Deficiency / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016572:Cyclosporine; D008274:Magnesium; D016559:Tacrolimus