Department of Biomolecular and Sports Sciences, Coventry University, Coventry, UK.
J Antimicrob Chemother. 2009 Nov;64(5):1002-7. doi: 10.1093/jac/dkp335. Epub 2009 Sep 11.
Interaction of antiretrovirals with drug transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), breast cancer resistance protein (BCRP) and solute carrier organic anion transporter (SLCO) may influence the emergence of viral mutants by altering intracellular drug concentrations. Here we characterize the effect of transporter expression in a variety of cell types such as control CEM, CEM(VBL) (P-gp-overexpressing), CEM(E1000) (MRP1-overexpressing), MT4, control MDCKII, MDCKII(MDR1) (P-gp-overexpressing) and peripheral blood mononuclear cells (PBMCs) on the uptake of [(14)C]efavirenz and [(3)H]nevirapine. We also investigated the lipophilicity of [(14)C]efavirenz and [(3)H]nevirapine.
The expression of P-gp, MRP1, MRP2, SLCO1A2, 1B1, 1B3, 2B1, 3A1 and 4A1 was assessed by PCR. Inhibitors of P-gp (XR9576, GF120918, dipyridamole) and MRP (MK571, frusemide, dipyridamole), and SLCO substrate or inhibitor (estrone-3-sulphate or montelukast, respectively) were used to study the role of drug transporters in the accumulation of [(14)C]efavirenz and [(3)H]nevirapine. Lipophilicity was measured by the octanol/saline partition coefficient.
CEM cells, MT4 cells and PBMCs express various SLCO isoforms, with SLCO3A1 detected in all of the cells. XR9576, dipyridamole and GF120918 had no effects on the accumulation of [(14)C]efavirenz, while MK571 and frusemide produced variable effects in the cells. The accumulation of [(14)C]efavirenz was significantly decreased in all the cells by montelukast and estrone-3-sulphate.
P-gp expression had no effect on the accumulation of [(14)C]efavirenz and [(3)H]nevirapine. MRP1/2 expression, lipophilicity and SLCO-like transporters (possibly SLCO3A1) may have greater influence on the accumulation of [(14)C]efavirenz than [(3)H]nevirapine.
抗逆转录病毒药物与药物转运蛋白（如 P-糖蛋白（P-gp）、多药耐药相关蛋白（MRP）、乳腺癌耐药蛋白（BCRP）和溶质载体有机阴离子转运蛋白（SLCO））的相互作用可能通过改变细胞内药物浓度影响病毒突变体的出现。在此，我们描述了在各种细胞类型（如对照 CEM、CEM(VBL)（P-gp 过表达）、CEM(E1000)（MRP1 过表达）、MT4、对照 MDCKII、MDCKII(MDR1)（P-gp 过表达）和外周血单核细胞（PBMCs））中，转运蛋白表达对 [(14)C]efavirenz 和 [(3)H]nevirapine 摄取的影响。我们还研究了 [(14)C]efavirenz 和 [(3)H]nevirapine 的亲脂性。
通过 PCR 评估 P-gp、MRP1、MRP2、SLCO1A2、1B1、1B3、2B1、3A1 和 4A1 的表达。使用 P-gp 抑制剂（XR9576、GF120918、双嘧达莫）和 MRP 抑制剂（MK571、呋塞米、双嘧达莫）以及 SLCO 底物或抑制剂（雌酮-3-硫酸盐或孟鲁司特，分别）研究药物转运体在 [(14)C]efavirenz 和 [(3)H]nevirapine 积累中的作用。亲脂性通过辛醇/盐水分配系数测量。
CEM 细胞、MT4 细胞和 PBMCs 表达各种 SLCO 同工型，所有细胞均检测到 SLCO3A1。XR9576、双嘧达莫和 GF120918 对 [(14)C]efavirenz 的积累没有影响，而 MK571 和呋塞米在细胞中产生了不同的影响。所有细胞中的 [(14)C]efavirenz 积累均被孟鲁司特和雌酮-3-硫酸盐显著降低。
P-gp 表达对 [(14)C]efavirenz 和 [(3)H]nevirapine 的积累没有影响。MRP1/2 表达、亲脂性和类似 SLCO 的转运体（可能是 SLCO3A1）可能对 [(14)C]efavirenz 的积累比对 [(3)H]nevirapine 的积累有更大的影响。
