Kakumoto Mikio, Takara Kohji, Sakaeda Toshiyuki, Tanigawara Yusuke, Kita Tomoko, Okumura Katsuhiko
Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
Biol Pharm Bull. 2002 Dec;25(12):1604-7. doi: 10.1248/bpb.25.1604.
The multidrug transporter, MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs was examined in vitro by using the MDR1-overexpressing LLC-GA5-COL150 cells, which were established by transfection with human MDR1 cDNA into porcine kidney epithelial LLC-PK(1) cells. Amiodarone, its active metabolite monodesethyl-amiodarone (DEA), and quinidine markedly inhibited the basal-to-apical transport (renal secretion) of [(3)H]digoxin and increased the apical-to-basal transport (reabsorption), but cibenzoline and lidocaine showed slight inhibition of the transport, and disopyramide and mexiletin had no such effects. The IC(50) values for amiodarone, DEA and quinidine on [(3)H]digoxin transport in LLC-GA5-COL150 cells were 5.48 microM, 1.27 microM and 9.52 microM, respectively. These were comparable to, or only several times the achievable concentration in clinical use, suggesting that MDR1 could be responsible for the drug interaction between digoxin and amiodarone found in clinical reports and that DEA contributes the elevation of digoxin serum concentration. Similarly, dipyridamole altered the transport, but isosorbide showed only slight modification of the transport. The IC(50) value for dipyridamole was 40.0 microM, also only several times the achievable concentration in clinical use, indicating a risk of interaction.
利用通过将人MDR1 cDNA转染到猪肾上皮LLC-PK(1)细胞中建立的过表达MDR1的LLC-GA5-COL150细胞，在体外研究了多药转运体MDR1介导的地高辛与抗心律失常或抗心绞痛药物的相互作用。胺碘酮、其活性代谢物单去乙基胺碘酮（DEA）和奎尼丁显著抑制[(3)H]地高辛的基底到顶端转运（肾脏分泌），并增加顶端到基底转运（重吸收），但西苯唑啉和利多卡因对转运有轻微抑制作用，而丙吡胺和美西律则无此作用。胺碘酮、DEA和奎尼丁对LLC-GA5-COL150细胞中[(3)H]地高辛转运的IC(50)值分别为5.48 microM、1.27 microM和9.52 microM。这些值与临床使用中可达到的浓度相当，或仅为其几倍，这表明MDR1可能是临床报告中发现的地高辛与胺碘酮之间药物相互作用的原因，并且DEA导致地高辛血清浓度升高。同样，双嘧达莫改变了转运，但异山梨醇仅对转运有轻微影响。双嘧达莫的IC(50)值为40.0 microM，也仅为临床使用中可达到浓度的几倍，表明存在相互作用的风险。
