Peter K, Gambertoglio J G
Department of Clinical Pharmacy, University of California, San Francisco 94143-0622, USA.
Pharm Res. 1998 Jun;15(6):819-25. doi: 10.1023/a:1011956011207.
Dramatic reductions of viral load and increased survival have been achieved in patients infected with the Human Immunodeficiency Virus (HIV) with the introduction of combination antiretroviral therapy. Currently 11 agents including nucleoside reverse transcriptase inhibitors (RTI), non-nucleoside RTI and protease inhibitors are available for the use for treatment of HIV infection. Recent studies have demonstrated that certain combinations of these drugs are advantageous over their individual use as monotherapy with an even more sustained viral suppression. Much emphasis has therefore been put on studies evaluating the interactions of these different compounds. Especially the intracellular metabolism of nucleoside RTI has been evaluated to some extent, by both in vitro and in vivo studies. These compounds need to undergo phosphorylation to their active 5'-triphoshates involving several enzymatic steps and the nucleoside concentration in the plasma may not correlate with intracellular concentrations of active drug. It is therefore of great importance to study these drugs at an intracellular level in order to evaluate their efficacy. This review summarizes the intracellular phosphorylation of Zidovudine and other nucleoside analogs investigated by in vitro experiments and the efforts of measuring the active anabolites in vivo in cells isolated from HIV infected patients on nucleoside therapy.
随着联合抗逆转录病毒疗法的引入，感染人类免疫缺陷病毒（HIV）的患者实现了病毒载量的显著降低和生存率的提高。目前有11种药物可用于治疗HIV感染，包括核苷类逆转录酶抑制剂（RTI）、非核苷类RTI和蛋白酶抑制剂。最近的研究表明，这些药物的某些组合比单独使用单一疗法更具优势，能实现更持久的病毒抑制。因此，人们非常重视评估这些不同化合物之间相互作用的研究。特别是核苷类RTI的细胞内代谢已通过体外和体内研究在一定程度上进行了评估。这些化合物需要经过几个酶促步骤磷酸化为其活性5'-三磷酸形式，血浆中的核苷浓度可能与细胞内活性药物浓度不相关。因此，在细胞内水平研究这些药物以评估其疗效非常重要。本综述总结了通过体外实验研究的齐多夫定和其他核苷类似物的细胞内磷酸化情况，以及在接受核苷治疗的HIV感染患者分离的细胞中体内测量活性代谢物的研究成果。
