Chemistry Department, Wilkes University, Wilkes Barre, Pennsylvania 18766, USA.
Pharm Res. 2004 Mar;21(3):420-7. doi: 10.1023/B:PHAM.0000019294.03188.cf.
Side effects of diarrhea and steatorrhea diminish the therapeutic value of highly active antiretroviral therapy (HAART). We report in vitro studies of the effect of HAART drugs on the activity of pancrelipase, trypsin, and enterokinase and restoration of activity by subsequent addition of excess pancrelipase or colipase.
Commercial formulations of sixteen HAART drug formulations with solvent and four excipients were mixed with substrate. Activity of pancrelipase was recorded after addition of the enzyme; restoration of activity was monitored after addition of excess pancrelipase or colipase to the reaction mixture.
Five protease inhibitors (Agenerase solution, Agenerase capsules, Norvir, Viracept, Kaletra, and Fortovase) and the excipient TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) inhibited lipase significantly at or below physiological concentrations. Neither nucleoside reverse transcriptase inhibitors nor non-nucleoside reverse transcriptase inhibitors showed significant lipase inhibition at physiological levels. Addition of excess pancrelipase to the medium completely reversed inhibition by Agenerase, Fortovase, Norvir, and TPGS and reactivated lipase; it diminished inhibition by Kaletra and Viracept but did not completely restore activity. Addition of colipase reversed inhibition by Agenerase solution, Agenerase capsules, and TPGS; inhibition by Kaletra and Fortovase recovered slightly. No compounds tested inhibited trypsin or enterokinase.
These results justify evaluating protocols involving coadministration of buffered pancrelipase with protease inhibitors to reduce or eliminate diarrhea and steatorrhea in individuals being treated for HIV.
腹泻和脂肪泻等副作用降低了高效抗逆转录病毒疗法（HAART）的治疗价值。我们报告了 HAART 药物对胰凝乳蛋白酶、胰蛋白酶和肠激酶活性的体外研究，以及通过随后添加过量的胰凝乳蛋白酶或辅脂酶来恢复其活性的情况。
将十六种 HAART 药物制剂的商业配方与溶剂和四种赋形剂混合到基质中。添加酶后记录胰凝乳蛋白酶的活性；向反应混合物中添加过量的胰凝乳蛋白酶或辅脂酶后，监测活性的恢复情况。
五种蛋白酶抑制剂（Agenerase 溶液、Agenerase 胶囊、Norvir、Viracept、Kaletra 和 Fortovase）和赋形剂 TPGS（d-α-生育酚聚乙二醇 1000 琥珀酸酯）在生理浓度下显著抑制脂肪酶。核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂在生理水平下均未显示出显著的脂肪酶抑制作用。向培养基中添加过量的胰凝乳蛋白酶可完全逆转 Agenerase、Fortovase、Norvir 和 TPGS 的抑制作用，并使脂肪酶重新激活；它减弱了 Kaletra 和 Viracept 的抑制作用，但并未完全恢复其活性。添加辅脂酶可逆转 Agenerase 溶液、Agenerase 胶囊和 TPGS 的抑制作用；Kaletra 和 Fortovase 的抑制作用略有恢复。未测试的化合物抑制胰蛋白酶或肠激酶。
这些结果证明了评估与蛋白酶抑制剂联合使用缓冲胰凝乳蛋白酶方案的合理性，以减少或消除接受 HIV 治疗个体的腹泻和脂肪泻。
