MECHANISMS OF INDUCTIVE DRUG INTERACTIONS WITH ANTI-HIV PROTEASE INHIBITORS

抗 HIV 蛋白酶抑制剂诱导药物相互作用的机制

• 批准号: 6701462
• 负责人: JASHVANT D Unadkat
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701462
• 关键词: SDS polyacrylamide gel electrophoresis; antiAIDS agent; clinical research; cytochrome P450; drug interactions; drug metabolism; enzyme mechanism; human subject; ligands; liver cells; multidrug resistance; nelfinavir; polymerase chain reaction; protease inhibitor; ritonavir; western blottings

Anti-HIV protease inhibitors (PRIs) are frontline drugs in the treatment of AIDS, and are now routinely administered in combination with other anti-HIV drugs including other protease inhibitors, nucleoside (e.g. azidothymidine) and non-nucleoside reverse transcriptase inhibitors (e.g. delavirdine). PRIs are substrates of CYP3A enzymes and of the multidrug resistance (MDR) transporters, MDR1 and MRP2. A significant clinical problem encountered in prescribing PRIs is their propensity to produce clinically significant drug interactions, both inductive and inhibitory, with drugs routinely administered to people with AIDS. To date, the focus of studies on the mechanisms and extent of drug interactions with PRIs has been on the capacity of the PRIs to potently inhibit CYP3A enzymes, both in vitro and in vivo. However, little is known about the mechanisms by which PRIs induce clearance of various drugs, as well as the mechanisms by which they cause induction of their own clearance (autoinduction). Of the PRIs used in the clinic, clinically significant inductive drug interactions and autoinduction have been reported most frequently with ritonavir and nelfinavir. Inductive drug interactions and autoinduction by ritonavir are most surprising as ritonavir inactivates CYP3A enzymes in vitro and potently inhibits CYP3A4/5 in vivo, enzymes responsible for the clearance of ritonavir and other PRIs. Like rifampin, ritonavir appears to be a broad-spectrum inducer of enzymes and transporters. This observation is consistent with ritonavir being an excellent ligand/activator of the human orphan nuclear receptor, hPXR (pregnane X receptor). Surprisingly, nelfinavir is NOT a ligand/activator of hPXR, and yet it is an autoinducer and causes inductive drug interactions. Thus, we have hypothesized that ritonavir and nelfinavir autoinduce and cause inductive drug interactions via different mechanisms. Ritonavir mediates its inductive effects primarily by activating hPXR, while nelfinavir does so via other mechanisms (e.g. activating other orphan nuclear receptors). The specific aims of this proposal are directed towards testing this hypothesis and towards elucidating the mechanisms and extent of in vitro and in vivo induction by PRIs of CYP enzymes and MDR transporters. Specific Aims 1. To determine, using human hepatocytes and human intestinal cell lines, the CYP enzymes and MDR transporters that are significantly induced by PRIs. 2. To determine if CYPs and MDR transporters significantly induced by ritonavir and nelfinavir in vitro, are induced to a similar extent in vivo in humans. 3. To determine if known variants of the MDR1 gene determine the in vivo disposition of ritonavir and nelfinavir and, therefore, the in vivo induction by these PRIs of MDR transporters and CYP enzymes. To determine the molecular mechanisms by which CYP enzymes and MDR transporters are induced by ritonavir and nelfinavir.

抗HIV蛋白酶抑制剂（PRI）是治疗AIDS的一线药物，并且现在常规地与其他抗HIV药物组合施用，所述其他抗HIV药物包括其他蛋白酶抑制剂、核苷（例如叠氮胸苷）和非核苷逆转录酶抑制剂（例如地拉韦啶）。PRI是CYP 3A酶和多药耐药（MDR）转运蛋白MDR 1和MRP 2的底物。在处方PRI时遇到的一个重要临床问题是它们倾向于产生临床上重要的药物相互作用，包括诱导和抑制， 艾滋病患者的常规用药。迄今为止，关于药物与PRI相互作用的机制和程度的研究重点是PRI在体外和体内有效抑制CYP 3A酶的能力。然而，关于PRI诱导各种药物清除的机制以及它们诱导自身清除（自诱导）的机制知之甚少。在用于 利托那韦和奈非那韦最常报告临床、临床显著的诱导药物相互作用和自身诱导。利托那韦的诱导性药物相互作用和自身诱导是最令人惊讶的，因为利托那韦在体外灭活CYP 3A酶，并在体内有效抑制CYP 3A 4/5，这些酶负责利托那韦和其他PRI的清除。与利福平一样，利托那韦似乎是酶和转运蛋白的广谱诱导剂。这一观察结果与利托那韦是一种优秀的人类孤儿配体/激活剂一致。 核受体，hPXR（α-羟色胺X受体）。令人惊讶的是，奈非那韦不是hPXR的配体/激活剂，但它是一种自诱导剂，可引起诱导性药物相互作用。因此，我们假设利托那韦和奈非那韦通过不同的机制自我诱导和引起诱导性药物相互作用。利托那韦主要通过激活hPXR介导其诱导作用，而奈非那韦通过其他机制（例如激活其他孤儿核受体）介导其诱导作用。本提案的具体目的是针对测试这一假设，并阐明体外和体内诱导的机制和程度的PRI的酶和MDR转运蛋白。 具体目标 1.使用人肝细胞和人肠细胞系，确定PRI显著诱导的MDR酶和MDR转运蛋白。 2.确定利托那韦和奈非那韦在体外显著诱导的CYP和MDR转运蛋白在人体内的诱导程度是否相似。 3.确定MDR 1基因的已知变体是否决定利托那韦和奈非那韦的体内处置，从而决定这些PRI对MDR转运蛋白和MDR酶的体内诱导。 确定利托那韦和奈非那韦诱导MDR酶和MDR转运蛋白的分子机制。