Servais Aude, Lechat Philippe, Zahr Noël, Urien Saik, Aymard Guy, Jaudon Marie Chantal, Deray Gilbert, Isnard Bagnis Corinne
Service de néphrologie, CHU Pitié-Salpétrière, Paris, France.
Nephrol Ther. 2005 Nov;1(5):296-300. doi: 10.1016/j.nephro.2005.06.011. Epub 2005 Oct 21.
Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.
阿德福韦通过有机阴离子转运体（OAT1）以及多药耐药蛋白（MRP2、4和5）进行转运。我们研究了在大鼠中丙磺舒抑制转运体后以及在缺乏MRP2的TR-大鼠中阿德福韦的清除情况。在丙磺舒或安慰剂治疗后，通过群体建模（NONMEM）研究了10mg/kg阿德福韦的药代动力学。经尿液排泄的药物比例较低。在丙磺舒处理的TR-大鼠中（0.03±0.02升/小时），阿德福韦的肾清除率显著低于正常对照组（0.09±0.05升/小时）、正常丙磺舒组（0.10±0.07升/小时）以及TR-对照组大鼠（0.13±0.07升/小时）（P<0.05）。在大鼠体内，单独的MRP2突变并不影响阿德福韦的清除，这表明MRP2在阿德福韦的分泌过程中不发挥关键作用。对转运体进行额外的药理学抑制会降低肾清除率，这可能反映出当缺乏MRP2时激活的补偿性转运机制受到了抑制。
