Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp) related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123) were conducted in the absence (control group) and presence (experimental groups) of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M) increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate) changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies.

中文翻译：

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辅料-药物药代动力学相互作用：崩解剂对切除猪肠道组织外排的影响

药用辅料最初设计为药理学惰性。然而，发现某些赋形剂对药物药效学和/或药代动力学有改变作用。药代动力学相互作用可能由外排转运蛋白、细胞间紧密连接和/或代谢酶等的调节引起。在这项研究中，评估了来自不同化学类别的五种崩解剂的 P-糖蛋白 (P-gp) 相关抑制和紧密连接调节作用。模型化合物罗丹明 123 (R123) 的双向转运研究是在没有（对照组）和存在（实验组）四种浓度的每种选择的崩解剂穿过切除的猪空肠组织的情况下进行的。结果表明，一些选定的崩解剂（如 Ac-di-sol® 和 Kollidon® CL-M）由于抑制 P-gp 相关的流出而增加了 R123 的吸收转运，而另一种崩解剂（例如海藻酸钠）由于抑制 P-gp 和瞬态反应而改变了 R123 的转运以浓度依赖性方式打开紧密连接。可以得出结论，一些崩解剂与肠上皮的共同应用可能导致与易受 P-gp 相关外排影响的药物的药代动力学相互作用。然而，这些体外渗透发现的临床意义应通过体内研究来证实。海藻酸钠）由于抑制 P-gp 以及以浓度依赖性方式短暂打开紧密连接而改变了 R123 的转运。可以得出结论，一些崩解剂与肠上皮的共同应用可能导致与易受 P-gp 相关外排影响的药物的药代动力学相互作用。然而，这些体外渗透发现的临床意义应通过体内研究来证实。海藻酸钠）由于抑制 P-gp 以及以浓度依赖性方式短暂打开紧密连接而改变了 R123 的转运。可以得出结论，一些崩解剂与肠上皮的共同应用可能导致与易受 P-gp 相关外排影响的药物的药代动力学相互作用。然而，这些体外渗透发现的临床意义应通过体内研究来证实。