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:
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Authors | Jun Fujishiro, Shinji Kudou, Satomi Iwai, Masafumi Takahashi, Yoji Hakamata, Miki Kinoshita, Satoru Iwanami, Shigeru Izawa, Tokutaro Yasue, Kohei Hashizume, Takashi Murakami, Eiji Kobayashi |
Journal | Transplantation
(Transplantation)
Vol. 82
Issue 6
Pg. 804-12
(Sep 27 2006)
ISSN: 0041-1337 [Print] United States |
PMID | 17006328
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- KRP-203
- Receptors, Lysosphingolipid
- Sulfhydryl Compounds
- Cyclosporine
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Topics |
- Animals
- Calcium Signaling
(physiology)
- Cyclosporine
(therapeutic use)
- Drug Therapy, Combination
- Graft Survival
- Heart Rate
(drug effects)
- Kidney Transplantation
(immunology)
- Major Histocompatibility Complex
- Male
- Rats
- Rats, Inbred F344
- Receptors, Lysosphingolipid
(agonists)
- Sulfhydryl Compounds
(therapeutic use)
- Transplantation, Homologous
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