PF-8380 inhibits rat autotaxin with an IC50 of 1.16 nM when tested with the FS-3 substrate. The efficacy of PF-8380 is sustained when the enzyme, derived from fetal fibroblasts, is combined with lysophosphatidyl choline (LPC) as the substrate. In human whole blood incubated with PF-8380 for 2 hours, autotaxin inhibition occurs with an IC50 of 101 nM[1]. Autotaxin (ATX), an enzyme with lysophospholipase D (lysoPLD) activity, converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). Treatment of GL261 and U87-MG cells with 1 μM PF-8380 prior to 4 Gy irradiation leads to reduced clonogenic survival, lowered migration (33% in GL261; P=0.002 and 17.9% in U87-MG; P=0.012), decreased invasion (35.6% in GL261; P=0.0037 and 31.8% in U87-MG; P=0.002), and reduced radiation-induced Akt phosphorylation[2].
体内研究
The pharmacokinetic properties of PF-8380 are assessed following an intravenous dose of 1 mg/kg and oral doses ranging from 1 to 100 mg/kg over a 24-hour period. PF-8380 exhibits a mean clearance rate of 31 mL/min/kg, a steady-state distribution volume of 3.2 L/kg, and an effective half-life of 1.2 hours. Its oral bioavailability is moderate, varying between 43 and 83%. Plasma concentrations rise with increasing single oral doses; however, the maximum concentration (Cmax) increases roughly proportionally with doses from 1 to 10 mg/kg and less than proportionally from 10 to 100 mg/kg. Drug exposure, as estimated by the area under the curve (AUC), is approximately proportional to the dose and remains linear up to 100 mg/kg. Levels of plasma C16:0, C18:0, and C20:0 LPA are measured immediately after collection. The most significant reduction in LPA levels occurs at the 3 mg/kg dose within 0.5 hours, with all LPA levels returning to or surpassing baseline by 24 hours[1].
Treatment with 10 mg/kg PF-8380 modestly increases tumor-associated vascularity by 20% (P=0.497). However, administering PF-8380 45 minutes before a 4 Gy irradiation reduces vascularity by nearly 48% compared to control (P=0.031), and by 65% relative to mice that underwent radiation alone (P=0.011)[2].
体外研究
PF-8380 inhibits rat autotaxin with an IC50 of 1.16 nM when tested with the FS-3 substrate. The efficacy of PF-8380 is sustained when the enzyme, derived from fetal fibroblasts, is combined with lysophosphatidyl choline (LPC) as the substrate. In human whole blood incubated with PF-8380 for 2 hours, autotaxin inhibition occurs with an IC50 of 101 nM[1].
Autotaxin (ATX), an enzyme with lysophospholipase D (lysoPLD) activity, converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). Treatment of GL261 and U87-MG cells with 1 μM PF-8380 prior to 4 Gy irradiation leads to reduced clonogenic survival, lowered migration (33% in GL261; P=0.002 and 17.9% in U87-MG; P=0.012), decreased invasion (35.6% in GL261; P=0.0037 and 31.8% in U87-MG; P=0.002), and reduced radiation-induced Akt phosphorylation[2].
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