Reparixin L-lysine salt

Reparixin L-lysine salt is an inhibitor of interleukin 8 receptor alpha (CXCR1) and beta (CXCR2) with IC50 value of 5.6 nM and 80 nM respectively [1].

CXCR1 and 2 belong to class A of 7-transmembrane G protein coupled receptor, and they share 78% amino acid identity. They are specific receptors for interleukin-8 which is a chemokine. They are mainly expressed in the neutrophils, where they mediate neutrophil migration to the site of inflammation. In addition, they are also involved in tumor aggressive growth and metastasis of human malignant melanoma.

Structural and biochemical study identified that Reparixin L-lysine salt had non-competitive allosteric interaction with CXCR1 and 2, by which blocking CXCR1 and CXR2 in an inactive conformation, and thus suppressed receptor-induced intracellular signaling cascade and cellular response [2]. When CXCR1 were expressed in L1.2 cells, cell migration induced by 10 nM CXC8 was significantly inhibited by reparixin L-lysine salt [1].

In mouse model, treatment of reparixin L-lysine salt after introduction of injury significantly (15 mg/ kg/ day for 7 days) suppressed secondary degeneration by reducing CXC8-dependent oligodendrocyte apoptosis, migration to the injury site of neutrophils and ED-1-positive cells. Additionally, the level of macrophage-inflammatory protein-2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1 beta was also reduced, and the proliferation of glial fibrillary acidic protein-positive cells was significantly reduced [2].

In mouse ischemia model, pre-treatment with reparixin reduced the motor deficits, myeloperoxidase activity and IL-1b level. Furthermore, ischemic injury was also attenuated [3].

References:
[1] Moriconi A et al. , Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem. 2007, 50(17): 3984-4002.
[2] Gorio A, Madaschi L, Zadra G, Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of functionafter traumatic lesion to the spinal cord.  J Pharmacol Exp Ther. 2007, 322(3): 973-981.
[3] Sousa L F, Coelho F M, Rodrigues D H, Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice.  Clinics (Sao Paulo). 2013, 68(3): 391-394.

Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog.[Pubmed:16854780]

Xenobiotica. 2006 May;36(5):419-40.

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-Reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.