Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation.
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.
Fujishiro
Jun
J
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
Kudou
Shinji
S
Iwai
Satomi
S
Takahashi
Masafumi
M
Hakamata
Yoji
Y
Kinoshita
Miki
M
Iwanami
Satoru
S
Izawa
Shigeru
S
Yasue
Tokutaro
T
Hashizume
Kohei
K
Murakami
Takashi
T
Kobayashi
Eiji
E
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
C501899:KRP-203; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds; D016572:Cyclosporine