P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds[1]. P-glycoprotein is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death[2]. Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function for the body against foreign substances[3]. N-(4-Fluorophenyl)-4-phenyl-2-thiazolami (UCLA GP130 2) is a potent, brain-penetrant and orally active GP130 receptor agonist. UCLA GP130 2 treatment showed a 2-fold increase in phosphorylation of STAT3 within 10 min at its regulatory Tyr705 site in SH-SY5Y cells. UCLA GP130 2 treatment increases phosphorylation of AKT at its regulatory Thr308 site and phosphorylation of ERK1/2 at its regulatory Thr202/Tyr204 site in the serum free media condition in SH-SY5Y cells, and in primary cortical neurons. For UCLA GP130 2, mice are dosed orally at 10 or 30 mg/kg, or injected subcutaneously at 10 mg/kg, and euthanized after 1, 2, 4, 6, and 8 h post dose. At 2 h after SQ delivery at 10 mg/kg the brain Cmax is 161 ng/g while dosing at 30 mg/kg orally, results in the brain Cmax of 156 ng/g (0.57 μM). The brain to plasma ratio for 2 is ∼4:1 for oral 30 mg/kg and ∼7.5:1 for 10 mg/kg SQ injection[4].
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