Effects of nelfinavir and its M8 metabolite on lymphocyte P-glycoprotein activity during antiretroviral therapy
Effects of nelfinavir and its M8 metabolite on lymphocyte P-glycoprotein activity during antiretroviral therapy
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DOI：
10.1067/mcp.2003.11
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发表时间：
2003-01-01
影响因子：
6.7
通讯作者：
Haas, DW
中科院分区：
文献类型：
--
作者：
Donahue, JP;Dowdy, D;Haas, DW
外排泵P-糖蛋白减少药物渗透到细胞和组织中。为了确定奈非那韦或其代谢产物是否抑制健康志愿者淋巴细胞中的P-糖蛋白，将人类免疫缺陷病毒阴性供体的全血细胞在离体加入奈非那韦或其M8代谢产物的人血浆中或接受奈非那韦的人类免疫缺陷病毒阳性患者的血浆中孵育。纯化的奈非那韦和M8的50% P-糖蛋白抑制浓度对CD 4（+）T细胞分别为10.9 mumol/L和29.5 mumol/L，对CD 8（+）T细胞分别为19.3 mumol/L和>48 mumol/L。46例接受奈非那韦治疗的患者中有27例（59%）的血浆中存在显著的抑制活性。血浆奈非那韦浓度与对CD 4（+）（p = 0.85，P <0.0001）和CD 8（+）（p = 0.83，P <0.0001）T细胞的抑制百分比相关。M8浓度与抑制和奈非那韦浓度均弱相关。根据我们在暴露于人类免疫缺陷病毒阳性患者血浆的健康志愿者淋巴细胞中的发现，我们认为接受奈非那韦治疗人类免疫缺陷病毒的患者的CD 4（+）和CD 8（+）淋巴细胞可能具有受奈非那韦血浆浓度抑制的P-糖蛋白。
The efflux pump P-glycoprotein decreases drug penetration into cells and tissues. To determine whether nelfinavir or its metabolites inhibit P-glycoprotein in lymphocytes from a healthy volunteer, whole blood cells from human immunodeficiency virus-negative donors were incubated either in human plasma to which nelfinavir or its M8 metabolite were added ex vivo or in plasma from human immunodeficiency virus-positive patients receiving nelfinavir. The 50% P-glycoprotein inhibitory concentrations of purified nelfinavir and M8 were 10.9 mumol/L and 29.5 mumol/L, respectively, for CD4(+) T cells and 19.3 mumol/L and >48 mumol/L, respectively, for CD8(+) T cells. Significant inhibitory activity was present in plasma from 27 of 46 patients (59%) receiving nelfinavir. Plasma nelfinavir concentrations correlated with percent inhibition on CD4(+) (p = 0.85, P < .0001) and CD8(+) (p = 0.83, P < .0001) T cells. The M8 concentrations correlated weakly with both inhibition and nelfinavir concentrations. On the basis of our findings in lymphocytes from a healthy volunteer exposed to plasma from human immunodeficiency virus-positive patients, we believe it is likely that CD4(+) and CD8(+) lymphocytes in patients receiving nelfinavir as therapy for human immunodeficiency virus may have P-glycoprotein inhibited by plasma concentrations of nelfinavir.