リンパ球細胞におけるニンテダニブの細胞内濃度に対するＰ糖タンパク質阻害の影響

抄録

P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects. To date the information on P-gp-mediated drug interaction at lymphocytes is limited. We analyzed the importance of P-gp in lymphocytes using peripheral blood mononuclear cells (PBMCs) together with K562, K562/Adr, and K562/Vin cells, which have P-gp expression levels in lymphocytes, ranging from healthy subjects to treatment-resistant RA patients, as cell models, and dexamethasone, nintedanib and apafant as weak, moderate and good P-gp substrates, respectively. Cell accumulation of the P-gp substrates, apafant and nintedanib, in healthy PBMCs and the three K562 cells decreased with increasing P-gp levels but dexamethasone accumulation in K562/Adr was comparable to that in cells having low P-gp levels (healthy PBMCs and K562). Cell accumulation of apafant, nintedanib and dexamethasone in cells having low P-gp levels was not significantly changed in the presence of the P-gp inhibitors at therapeutic concentrations. However, accumulation increased to a maximum to 1.2-1.4 fold for apafant and nintedanib and 1.04-fold for dexamethasone in K562/Adr cells having higher P-gp expression than in PBMCs of treatment-resistant RA patients. These results suggest that P-gp controls the cellular concentration of P-gp substrates in PBMCs or K562 cell lines, but cellular concentration of a weak P-gp substrate would not be apparently affected even in cells with a sufficient P-gp expression.