CYP3A和P-糖蛋白对布格呋喃在大鼠小肠吸收的影响

本研究采用大鼠小肠在体单向 (single-pass) 灌流模型, 收集灌流后不同时间点灌流液和肠系膜静脉血, 应用GC-MS联用法测定灌注液和血浆中的布格呋喃含量, 并计算布格呋喃渗透系数［P_lumen = −(Q/2πrl) Ln(C_out/C_in) 和P_blood = (ΔM_B/Δt)/(2πrl)］, 从而反映布格呋喃的代谢变化。同时, 观察CYP3A选择性抑制剂醋竹桃霉素 (TAO)、CYP3A和P-糖蛋白 (P-gp) 共同抑制剂环孢素A (CsA) 和P-gp选择性抑制剂LSN335984对布格呋喃自大鼠肠道吸收的影响。结果表明, 在大鼠小肠在体单向灌流模型中加入LSN335984、TAO和CsA后, 大鼠肠系膜静脉血中布格呋喃的累积量分别为73.4、82.9和98.3 pmol·cm⁻², 与对照组比较分别增加3.9倍、4.6倍和5.6倍, 代谢分别减少12%、11%和21%。提示CYP3A和P-gp选择性抑制剂可明显减少布格呋喃在大鼠肠道的首过效应, 促进布格呋喃的肠道吸收。由此可见, P-gp与CYP3A两者联合作用是引起布格呋喃口服生物利用度低的重要因素, 两者对布格呋喃小肠吸收均具有重要影响。

Effect of CYP3A and P-glycoprotein on the absorption of buagafuran in rat intestinal lumen

The rat single-pass intestinal perfusion model was applied to study the effect of CYP3A and P-glycoprotein on the absorption of buagafuran in lumen of rats.  Buagafuran concentrations in intestinal   perfusate and blood in vena mesenterica collected at different time points after perfusion were determined by GC-MS.  Permeability coefficient of buagafuran was calculated by the equation P_lumen = −(Q/2πrl)Ln(C_out/C_in) and P_blood = (ΔM_B/Δt)/(2πrl<C>)].  The effects of troleandomycin (TAO, CYP3A inhibitor), cyclosporin A (CYP3A/p-glycoprotein inhibitor) on the absorption of buagafuran in lumen were observed.  After rat single- pass intestinal perfusion, the cumulative amount of buagafuran in mesenteric vein of rat was 73.4, 82.9, and 98.3 pmol·cm⁻² and were increased 3.9, 4.6, and 5.6 fold by addition of inhibitor of P-gp (LSN335984), CYP3A (TAO) or P-gp and CYP3A (CsA), respectively.  Moreover, the metabolized fraction of buagafuran was decreased by 12%, 11% and 21% with inhibitors.  The results suggested that the poor bioavailability of buagafuran was mostly due to the interplay of P-gp and CYP3A on the absorption, transport and metabolism of buagafuran in  intestine of rats.