The intracellular pharmacology of antiretroviral protease inhibitors
The intracellular pharmacology of antiretroviral protease inhibitors
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DOI：
10.1093/jac/dkh487
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发表时间：
2004-12-01
影响因子：
5.2
通讯作者：
Back, DJ
中科院分区：
文献类型：
--
作者：
Ford, J;Khoo, SH;Back, DJ
抗逆转录病毒蛋白酶抑制剂（PI）的治疗药物监测（TDM）已被认为具有降低毒性和优化个体化治疗的潜力。然而，PI的主要靶点是感染HIV的细胞内。因此，临床结果最终必须与细胞内药物浓度相关，因为PI的抗病毒活性与体外细胞内浓度高度相关。细胞内药代动力学提供了关于药物在HIV复制发生的隔室中的处置的信息，并且与血浆数据相结合可能有助于理解与细胞抗性相关的治疗失败。因此，为了提高治疗效果，除了血浆药代动力学之外，还研究药物（如PI）的细胞内药代动力学是重要的。多药耐药转运蛋白可能通过外排机制导致细胞内药物浓度降低，从而促进保护区位点形成。然而，尽管最近的研究试图解决这个问题，但仍然缺乏转运蛋白导致临床耐药性的确凿证据。在有关主机和细胞因素，这篇评论认为涉及影响细胞内药物浓度的几个问题，并讨论了细胞内水平的PI最近发表的细胞研究。
Therapeutic drug monitoring (TDM) of antiretroviral protease inhibitors (PIs) has been suggested to have the potential to both reduce toxicity and optimize individual therapy. However, the major target of PIs is within cells infected with HIV. Therefore clinical outcome ultimately must be related to intracellular drug concentrations since antiviral activity of PIs is highly correlated with intracellular concentrations in vitro. Intracellular pharmacokinetics provides information regarding drug disposition in a compartment where HIV replication occurs and combined with plasma data may be useful in understanding therapeutic failure in relation to cellular resistance. In order to improve therapeutic efficacy, it is therefore important that the intracellular pharmacokinetics of drugs, such as PIs, is studied in addition to plasma pharmacokinetics. Multidrug resistance transporters may result in a lower cellular concentration of drug via an efflux mechanism, thus contributing to sanctuary site formation. However, conclusive proof that transporters contribute to clinical drug resistance is still lacking, although recent studies have attempted to address this issue. In relation to host and cellular factors, this review considers several issues involved in influencing intracellular drug concentrations and discusses the intracellular levels of PIs recently published from cellular studies.