Kurdziel Karen A, Kiesewetter Dale O, Carson Richard E, Eckelman William C, Herscovitch Peter
PET Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA.
J Nucl Med. 2003 Aug;44(8):1330-9.
Multidrug resistance (MDR) associated with increased expression and function of the P-glycoprotein (Pgp) efflux pump often causes chemotherapeutic failure in cancer. To provide insight into both the dynamics of the pump and the effects of MDR, we radiolabeled paclitaxel, a substrate for the Pgp pump, with (18)F to study MDR in vivo with PET. We obtained biodistribution and radiation dose estimates for (18)F-paclitaxel (FPAC) in monkeys and studied the effects of a Pgp blocker (XR9576, tariquidar) on FPAC kinetics.
Paired baseline and Pgp modulation (2 mg/kg XR9576) 4-h whole-body dynamic PET scans were obtained in 3 rhesus monkeys after injection of FPAC. Measured residence times were extrapolated to humans and radiation dose estimates were obtained using MIRDOSE3.1. The postmodulator area under the time-activity curves (AUCs) and Logan plot slopes, a measure of tracer distribution volume (equilibrium tissue-to-plasma ratio) that is inversely proportional to tracer efflux, were compared with baseline values to determine changes in FPAC distribution.
Cumulative activities of the organs sampled accounted for 80% of the injected dose. The critical organ is gallbladder wall (0.19 mGy/MBq [0.69 rad/mCi]), followed by liver (0.14 mGy/MBq [0.52 rad/mCi]); the effective dose is 0.022 mSv/MBq (0.083 rem/mCi). XR9576 preinfusion changed the Logan plot slope for liver by +104% (P = 0.02), lung by +87% (P = 0.11), and kidney by -14% (P = 0.08). Changes in the mean AUC (normalized to the plasma AUC) were +54% (P = 0.08), +97% (P = 0.04), and -12% (P = 0.02), respectively, for liver, lung, and kidney. No significant difference was found in the metabolite-corrected plasma AUC (normalized to the injected dose) between the baseline and XR9576 modulator studies (P = 0.69).
Under Radioactive Drug Research Committee guidelines, 266 MBq (7.2 mCi) FPAC can be administered to humans up to 3 times a year. The increase in FPAC accumulation in liver and lung after XR9576 is consistent with Pgp inhibition and demonstrates the potential of FPAC to evaluate MDR.
与P-糖蛋白（Pgp）外排泵表达增加和功能增强相关的多药耐药性（MDR）常导致癌症化疗失败。为深入了解该泵的动力学以及MDR的影响，我们用（18）F对Pgp泵的底物紫杉醇进行放射性标记，以通过正电子发射断层扫描（PET）在体内研究MDR。我们获得了猴体内（18）F-紫杉醇（FPAC）的生物分布和辐射剂量估计值，并研究了Pgp阻断剂（XR9576，他林洛尔）对FPAC动力学的影响。
给3只恒河猴注射FPAC后，进行配对的基线和Pgp调节（2mg/kg XR9576）4小时全身动态PET扫描。将测量的停留时间外推至人体，并使用MIRDOSE3.1获得辐射剂量估计值。将调节剂给药后时间-活度曲线（AUC）下的面积和洛根图斜率（一种与示踪剂分布体积成反比的示踪剂分布体积测量值，与示踪剂外排成反比）与基线值进行比较以确定FPAC分布变化。
所采集器官的累积活性占注射剂量的80%。关键器官是胆囊壁（0.19mGy/MBq[0.69rad/mCi]），其次是肝脏（0.14mGy/MBq[0.52rad/mCi]）；有效剂量为0.022mSv/MBq（0.083rem/mCi）。预输注XR9576使肝脏的洛根图斜率增加了104%（P = 0.02），肺增加了87%（P = 0.11），肾脏减少了14%（P = 0.08）。肝脏、肺和肾脏的平均AUC（相对于血浆AUC进行归一化）变化分别为+54%（P = 0.08）、+97%（P = 0.04）和-12%（P = 0.02）。基线和XR9576调节剂研究之间，经代谢物校正的血浆AUC（相对于注射剂量进行归一化）无显著差异（P = 0.69）。
根据放射性药物研究委员会的指导原则，每年可给人体注射高达3次266MBq（7.2mCi）的FPAC。XR9576给药后肝脏和肺中FPAC蓄积增加与Pgp抑制一致，并证明了FPAC评估MDR的潜力。
