P-GLYCOPROTEIN EXPRESSION AND FUNCTION IN HIV+ WOMEN

描述(摘要由申请人提供)：我们假设性别， 排卵功能和疾病可能影响P-糖蛋白(P-gp)表达 肠道和其他器官，如肝脏、子宫内膜和淋巴细胞， 从而调节HIV中的蛋白酶抑制剂(PI)的有效性 女人。P-gp的表达和功能随排卵功能和排卵周期的不同而不同。 最高水平出现在更年期和黄体中期。 疾病的严重程度也会影响P-gp的活性 妇女的组织(肝脏、肠道、淋巴细胞和子宫内膜)。 这反过来又会影响蛋白酶的药代动力学和药效学。 抑制物(PI)以及艾滋病毒疾病的进展。虽然差异很大 细胞色素P4503A(CyP3A)和P-gp药物的药代动力学 底物，如PI，表现为新陈代谢的差异，我们 相信这一最终结果是由P-gp功能和 活动，而不是通过人群中细胞色素P3A表达的差异。 项目IV有五个具体目标：i)确定肠道是否像 肝脏和子宫内膜，表现出不同水平的转运蛋白和酶 是由孕激素和/或雌激素调节的(这也是一种 衡量常用的细胞系，如肝脏和子宫内膜， 展示可能对检验假设有用的特征)；2) 了解淋巴细胞化验是否可以用作什么的简单模型 发生在子宫内膜、肠道和肝脏；3)检测是否已知 绝经前和绝经后妇女P-gp的差异 PI药物水平的差异；4)与排卵周期相关联 (卵泡早期、黄体中期和绝经后)和/或具有标志物的P1水平 病毒抗药性；以及5)确定四个参数的影响：(A) 排卵周期阶段(卵泡早期。黄体中期或 绝经后)，(B)种族(特别是非裔美国人与高加索人)， (C)有无艾滋病毒感染，以及(D)P-gp上的CD4计数水平 定量分析P-gp在组织活检中的表达 (肠道细胞、子宫内膜和外周血单核细胞)和 P-gp功能，通过PT药代动力学曲线测定。

Description (Abstract Provided by Applicant): We hypothesize that gender, ovulatory function and disease may affect P-glycoprotein (P-gp) expression in the intestine and other organs such as the liver, endometrium and lymphocytes, thereby modulating the effectiveness of protease inhibitors (PIs) in HIV+ women. P-gp expression and function varies with ovulatory function and phase. The highest levels occur during menopause and in the midluteal phase of the cycle; the severity of disease can also influence P-gp activity in various tissues in women (liver, gut, lymphocytes and endometrium). This in turn can affect the pharmacokinetics and pharmacodynamics of protease inhibitors (PIs) as well as the progression of HIV disease. While differences in pharmacokinetics of drugs that are cytochrome P4503A (CYP3A) and P-gp substrates, such as the PIs, are manifested as differences in metabolism, we believe that this end result is regulated by differences in P-gp function and activity rather than by differences in CYP3A expression across the population. Project IV has five specific aims: I) to determine if the intestine, like the liver and endometrium, exhibits variable levels of transporter and enzyme that are regulated by progestins and/or estrogen, (which will also serve as a measure as to how well commonly used cell lines, e.g., liver and endometrium, exhibit characteristics that may be useful in testing the hypothesis); 2) to learn whether an assay in lymphocytes might be used as a simple model for what occurs in the endometrium, intestine and liver; 3) to test whether known differences in P-gp between premenopausal and postmenopausal women translate into differences in PI drug levels; 4) to correlate ovulatory cycle phase (early follicular, midluteal and postmenopausal) and/or P1 levels with markers of viral resistance; and 5) to determine the effects of four parameters: (a) stage of ovulatory cycle phase (early follicular. midluteal or postmenopausal), (b) ethnicity (particularly African American vs. Caucasian), (c) presence vs. absence of HIV infection, and (d) CD4 count strata on P-gp expression, as measured by quantitative analysis of P-gp in tissue biopsies (intestinal cells, endometrium and peripheral blood mononuclear cells) and P-gp function, as measured by PT pharmacokinetic profiles.