Janneh Omar, Anwar Tariq, Jungbauer Christof, Kopp Stefan, Khoo Saye H, Back David J, Chiba Peter
Department of Biomolecular and Sport Sciences, Coventry University, Coventry, UK.
Antivir Ther. 2009;14(7):965-74. doi: 10.3851/IMP1399.
Drug efflux (for example, P-glycoprotein [P-gp], multidrug resistance-associated proteins [MRPs] and breast cancer resistance protein [BCRP]) and influx (for example, human organic anion transporting polypeptide [hOCTP] or human organic anion transporting polypeptide [hOATP]) transporters alter the cellular concentrations of some HIV protease inhibitors (HPIs). Here, we studied the lipophilicity and uptake of [(3)H]-atazanavir (ATV) in CEM (parental), CEM(VBL) (P-gp-overexpressing), CEM(E1000) (MRP1-overexpressing) and peripheral blood mononuclear cells (PBMCs), and evaluate the effects of modulators of drug transporters on uptake.
Lipophilicity was measured by octanol/saline partition method. The influence of influx/efflux transporters on uptake was evaluated in the absence and presence of inhibitors of P-gp (GPV031), P-gp/BCRP (tariquidar and GF120918), P-gp/MRP1 (dipyridamole and daidzein), MRP1/2 (frusemide and genistein), hOATP/hOCTP (estrone-3-sulfate [E-3-S]) and hOATP/hOCTP/MRP (probenecid). The effects of a number of HPIs on uptake were also evaluated. Data from digitonin permeabilized cells allowed the evaluation of the contribution of cellular binding to total drug uptake, whereas the inhibitory effect of ATV on P-gp was assessed by daunomycin efflux/uptake assays.
[(3)H]-ATV is lipophilic and accumulates in the cultured cells as follows: CEM>CEM(E1000)>CEM(VBL). Tariquidar, GF120918 and daidzein significantly increased the uptake of [(3)H]-ATV in the cultured cells. By contrast, only daidzein and tipranavir significantly increased uptake in PBMCs, with tariquidar and frusemide devoid of effects, whereas dipyridamole, E-3-S, GPV031 and genistein significantly decreased accumulation. ATV inhibits P-gp activity; manipulation of uptake with digitonin suggests binding of [(3)H]-ATV to P-gp.
[(3)H]-ATV is lipophilic, a P-gp, MRP and hOATP substrate and an inhibitor of P-gp. Concomitant administration of ATV with drugs and dietary components (for example, daidzein and genistein) that interact with these transporters could alter its pharmacokinetics.
药物外排转运体（例如P-糖蛋白[P-gp]、多药耐药相关蛋白[MRPs]和乳腺癌耐药蛋白[BCRP]）和内流转运体（例如人有机阴离子转运多肽[hOCTP]或人有机阴离子转运多肽[hOATP]）会改变某些HIV蛋白酶抑制剂（HPIs）的细胞内浓度。在此，我们研究了[³H] - 阿扎那韦（ATV）在CEM（亲代细胞）、CEM(VBL)（过表达P-gp）、CEM(E1000)（过表达MRP1）和外周血单核细胞（PBMCs）中的亲脂性和摄取情况，并评估了药物转运体调节剂对摄取的影响。
通过辛醇/盐水分配法测量亲脂性。在不存在和存在P-gp抑制剂（GPV031）、P-gp/BCRP抑制剂（他林洛尔和GF120918）、P-gp/MRP1抑制剂（双嘧达莫和大豆苷元）、MRP1/2抑制剂（呋塞米和染料木黄酮）、hOATP/hOCTP抑制剂（硫酸雌酮[E-3-S]）以及hOATP/hOCTP/MRP抑制剂（丙磺舒）的情况下，评估内流/外排转运体对摄取的影响。还评估了多种HPIs对摄取的影响。来自洋地黄皂苷通透细胞的数据可用于评估细胞结合对总药物摄取的贡献，而通过柔红霉素外排/摄取试验评估ATV对P-gp的抑制作用。
[³H] - ATV具有亲脂性，并按以下顺序在培养细胞中蓄积：CEM > CEM(E1000) > CEM(VBL)。他林洛尔、GF120918和大豆苷元显著增加了培养细胞中[³H] - ATV的摄取。相比之下，只有大豆苷元和替拉那韦显著增加了PBMCs中的摄取，他林洛尔和呋塞米无此作用，而双嘧达莫、E-3-S、GPV031和染料木黄酮显著降低了蓄积。ATV抑制P-gp活性；用洋地黄皂苷处理摄取情况表明[³H] - ATV与P-gp结合。
[³H] - ATV具有亲脂性，是P-gp、MRP和hOATP的底物，也是P-gp的抑制剂。将ATV与与这些转运体相互作用的药物和膳食成分（例如大豆苷元和染料木黄酮）同时给药可能会改变其药代动力学。
