Nakajima M, Nakanishi J, Hori M, Gemba M
J Pharmacobiodyn. 1984 Nov;7(11):830-5. doi: 10.1248/bpb1978.7.830.
Previous results (J. Pharm. Dyn., 7, 342, 1984) from this laboratory indicated that papaverine, a classical phosphodiesterase inhibitor, inhibited the transport of organic anions such as p-aminohippurate (PAH) and urate in rat kidney cortical slices. The transport of papaverine itself, an organic cationic drug, in the kidney is not yet understood. The purpose of this study was to examine the interaction of papaverine with incubated slices and basolateral membrane vesicles prepared from rat kidney cortex, in terms of the possibility of the intracellular action of papaverine in kidney cells. Papaverine was taken up against a concentration gradient by kidney cortical slices and by liver slices. The uptake of papaverine by the former slices was depressed by hypothermia and anoxia with metabolic inhibitors, but that of the drug by the latter slices was not affected by hypothermic condition. Tetraethylammonium (TEA) as a prototype for organic cationic drugs did not depress papaverine transport. TEA also had no effect on the inhibitory effect of papaverine on PAH accumulation in kidney cortical slices. Papaverine, however, inhibited TEA accumulation prominently. Kinetic studies using the slices indicated that papaverine increased the Km for TEA accumulation and decreased Vmax. Then, papaverine inhibition was a "mixed type". TEA uptake by basolateral membrane vesicles was markedly inhibited by papaverine, but PAH uptake by the vesicles was not affected by the drug. The present results indicate that papaverine may be at least partly transported by the same system which handles TEA, but some aspect of the transport system for papaverine may be qualitatively different from that for TEA. Additional studies are required, however, to unequivocally establish the relationships between papaverine and TEA renal transport mechanisms.
本实验室之前的研究结果（《药物动力学杂志》，第7卷，第342页，1984年）表明，经典的磷酸二酯酶抑制剂罂粟碱可抑制大鼠肾皮质切片中对氨基马尿酸（PAH）和尿酸盐等有机阴离子的转运。罂粟碱本身作为一种有机阳离子药物，其在肾脏中的转运情况尚不清楚。本研究的目的是从罂粟碱在肾细胞内发挥作用的可能性方面，研究罂粟碱与大鼠肾皮质制备的孵育切片和基底外侧膜囊泡之间的相互作用。罂粟碱可通过肾皮质切片和肝切片逆浓度梯度摄取。低温以及使用代谢抑制剂造成的缺氧会抑制前者切片对罂粟碱的摄取，但后者切片对该药物的摄取不受低温条件影响。作为有机阳离子药物原型的四乙铵（TEA）不会抑制罂粟碱的转运。TEA对罂粟碱抑制肾皮质切片中PAH蓄积的作用也没有影响。然而，罂粟碱显著抑制TEA的蓄积。使用切片进行的动力学研究表明，罂粟碱增加了TEA蓄积的Km值并降低了Vmax。因此，罂粟碱的抑制作用属于“混合型”。罂粟碱可显著抑制基底外侧膜囊泡对TEA的摄取，但该药物对囊泡摄取PAH没有影响。目前的研究结果表明，罂粟碱可能至少部分通过处理TEA的同一系统进行转运，但罂粟碱转运系统的某些方面在性质上可能与TEA的不同。然而，还需要进一步研究来明确确立罂粟碱与TEA肾脏转运机制之间的关系。
