Ford J, Meaden E R, Hoggard P G, Dalton M, Newton P, Williams I, Khoo S H, Back D J
Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Block H, First Floor, Liverpool L69 3GF.
J Antimicrob Chemother. 2003 Sep;52(3):354-8. doi: 10.1093/jac/dkg381. Epub 2003 Aug 13.
Increased expression of multidrug resistance transporters, such as P-glycoprotein (P-gp), has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites and tissue compartments.
To investigate the effect of PIs on the surface lymphocyte expression of P-gp in vitro and in vivo.
Peripheral blood mononuclear cells (PBMCs) were isolated from healthy subjects (n = 15) and incubated (72 h) with 10 microM of each PI studied (saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir), or dimethyl sulphoxide (DMSO) control. PBMCs were also isolated from HIV-infected subjects (n = 50; viral load <50 copies/mL) on a PI- or a non-PI-containing combination antiretroviral regimen. P-gp expression was analysed by flow cytometry.
No differences in surface P-gp expression on lymphocytes, CD4+ or CD8+ lymphocyte subsets were observed following incubation with 10 microM saquinavir, ritonavir, indinavir, amprenavir or lopinavir in vitro. Nelfinavir, however, increased P-gp expression. In vivo, no difference in P-gp expression on total lymphocytes was observed between patients receiving a PI-containing regimen [saquinavir n = 9, ritonavir n = 6, nelfinavir n = 7, indinavir n = 7 and lopinavir/ritonavir n = 13, and two nucleoside reverse transcriptase inhibitors (NRTIs)] and patients receiving a control regimen of three NRTIs alone (n = 8).
This study suggests that, of the PIs, only nelfinavir increases P-gp expression in vitro, and in vivo the PI class of antiretrovirals do not increase P-gp expression on lymphocytes. It is clear that factors other than PI induction are important in the inter-individual variability in the lymphocyte expression of P-gp.
多药耐药转运蛋白（如P-糖蛋白，P-gp）表达增加被认为是某些细胞内位点和组织隔室中蛋白酶抑制剂（PI）可用性降低的潜在机制。
研究蛋白酶抑制剂在体外和体内对淋巴细胞表面P-gp表达的影响。
从健康受试者（n = 15）中分离外周血单个核细胞（PBMC），并与所研究的每种PI（沙奎那韦、利托那韦、奈非那韦、茚地那韦、安普那韦和洛匹那韦）10μM或二甲亚砜（DMSO）对照物一起孵育（72小时）。PBMC也从接受含PI或不含PI的联合抗逆转录病毒方案的HIV感染受试者（n = 50；病毒载量<50拷贝/mL）中分离。通过流式细胞术分析P-gp表达。
在体外与10μM沙奎那韦、利托那韦、茚地那韦、安普那韦或洛匹那韦孵育后，淋巴细胞、CD4 +或CD8 +淋巴细胞亚群表面P-gp表达未观察到差异。然而，奈非那韦增加了P-gp表达。在体内，接受含PI方案（沙奎那韦n = 9、利托那韦n = 6、奈非那韦n = 7、茚地那韦n = 7和洛匹那韦/利托那韦n = 13，以及两种核苷类逆转录酶抑制剂（NRTIs））的患者与仅接受三种NRTIs对照方案（n = 8）的患者之间，总淋巴细胞上P-gp表达未观察到差异。
本研究表明，在蛋白酶抑制剂中，只有奈非那韦在体外增加P-gp表达，在体内抗逆转录病毒药物的PI类不会增加淋巴细胞上P-gp表达。很明显，PI诱导以外的因素在淋巴细胞P-gp表达的个体间差异中很重要。
