P-GLYCOPROTEIN EXPRESSION AND FUNCTION IN HIV+ WOMEN

描述（申请人提供的摘要）：我们假设性别， 排卵功能和疾病可能会影响P-糖蛋白（P-gp）表达， 肠和其他器官如肝脏、子宫内膜和淋巴细胞， 从而调节蛋白酶抑制剂（PI）在HIV+ 妇女P-gp的表达和功能随排卵功能和排卵时相而变化。 最高水平发生在绝经期和黄体中期， 疾病的严重程度也会影响P-gp活性， 女性的组织（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 抑制剂（PI）以及HIV疾病的进展。虽然差异 细胞色素P4503 A（CYP 3A）和P-gp药物的药代动力学 底物，如PI，表现为代谢的差异，我们 认为这一最终结果是由P-gp功能的差异调节的， 活性而不是整个人群中CYP 3A表达的差异。 第四个项目有五个具体目标：一）确定肠道，如 肝脏和子宫内膜，表现出不同水平的转运蛋白和酶， 受孕激素和/或雌激素的调节，（这也将作为一种 测量常用的细胞系，例如，肝脏和子宫内膜， 表现出可能有助于检验假设的特征）; 2） 了解淋巴细胞中的检测是否可以用作一个简单的模型， 发生在子宫内膜、肠道和肝脏; 3）测试是否已知 绝经前和绝经后妇女之间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P1水平与标志物 病毒抗性;和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（特别是非裔美国人对高加索人）， (c)存在与不存在HIV感染，以及（d）P-gp的CD 4计数分层 表达，通过组织活检中P-gp的定量分析测定 （肠细胞、子宫内膜和外周血单核细胞）和 P-gp功能，通过PT药代动力学曲线测量。

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.