title: Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation.
abstract: BACKGROUND
  We demonstrate the long-term effectiveness of KRP-203 treatment in combination with a subtherapeutic dose of cyclosporine A (CsA) on rat renal allografts.
  
  
  METHODS
  We tested the effect of KRP-203 in combination with CsA using a rat skin allograft model. The Pharmacokinetic interaction between CsA and KRP-203 was evaluated. The selectivity of KRP-203 for sphingosine-1-phosphate (S1P)1 and S1P3 receptors were investigated in vitro. Heart rate alteration following bolus injection of phosphorylated KRP-203 (KRP-203-P) or FTY720 (FTY720-P) was also monitored in rats. Finally, the long-term effectiveness of KRP-203 in conjunction with a low dose of CsA was investigated in a rat renal transplantation model.
  
  
  RESULTS
  Administration of KRP-203 with CsA prolonged skin allograft survival. KRP-203 and CsA had no effect on the pharmacokinetics of the other. While FTY720-P activated both S1P1 and S1P3 receptors, KRP-203-P selectively activated S1P1, but not the S1P3 receptor (EC50:>1000 nM). Compared to FTY720-P, a tenfold higher dose of KRP-203-P was necessary to induce transient bradycardia. With a low dose of CsA (1 mg/kg/day), KRP-203 (0.3 mg/kg/day) significantly prolonged renal allograft survival (P<0.05, survival time: 9.8 days (CsA) vs. >27.4 days (CsA+KRP)). Although a higher dose of CsA (3 mg/kg/day) alone kept recipients alive, this caused severe renal graft dysfunction. Use of KRP-203 (3 mg/kg/day) in conjunction with CsA markedly improved graft function (P<0.05, creatinine clearance: 0.41+/-0.25 ml/min [CsA] vs. 1.15+/-0.16 ml/min [CsA+KRP]).
  
  
  CONCLUSIONS
  The selectivity of KRP-203 for S1P1 reduces the risk of bradycardia, and the combination therapy of KRP-203 with CsA represents a safe and effective strategy for use in renal transplantation.
authors.affiliation: Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fujishiro
authors.forename: Shinji
authors.initials: S
authors.lastname: Kudou
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwai
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hakamata
authors.forename: Miki
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwanami
authors.forename: Shigeru
authors.initials: S
authors.lastname: Izawa
authors.forename: Tokutaro
authors.initials: T
authors.lastname: Yasue
authors.forename: Kohei
authors.initials: K
authors.lastname: Hashizume
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006085:Graft Survival; D006339:Heart Rate / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D014184:Transplantation, Homologous
chemical_list: C501899:KRP-203; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds; D016572:Cyclosporine