Kabasakal L, Halaĉ M, Nisli C, Oguz O, Onsel C, Civi G, Uslu I
Cerrahpasa Medical Faculty, Istanbul, Turkey.
Clin Nucl Med. 2000 Jan;25(1):20-3. doi: 10.1097/00003072-200001000-00005.
The failure to cure persons with cancer is caused primarily by the development of drug resistance by overexpression of p-glycoprotein. Diverse groups of drugs have been identified, including cyclosporine A, which can reverse drug resistance by inhibiting P-glycoprotein transport. Tc-99m sestamibi is a substrate for P-glycoprotein. P-glycoprotein is normally expressed in biliary canalicular surfaces of hepatocytes and is responsible for the excretion of cationic metabolites from the liver. The aim of the current study was to evaluate the effect of cyclosporine A on the biological distribution of Tc-99m sestamibi in vivo.
Five patients with alopecia and two renal transplant patients who were treated with cyclosporine A were selected for the study. All patients were examined before and at least 2 weeks after administration of cyclosporine A. Tc-99m sestamibi scintigraphy was performed by obtaining planar abdominal images at 5, 30, 60, 120, and 180 minutes after injection, and the liver-heart ratios were calculated.
Plasma cyclosporine A, bilirubin levels, liver enzymes, and creatinine clearance values were obtained from all patients. In three, the plasma cyclosporine A level was increased to more than 400 pg/dl. The liver-heart ratio was increased significantly after cyclosporine A administration (P < 0.01). After cyclosporine A administration Tc-99m sestamibi excretion was delayed and the uptake in the liver was increased. The difference was 17% at 5 minutes and 38% at 180 minutes. Liver retention was greatest in patients with cyclosporine A toxicity.
With a limited number of patients, this study suggests that Tc-99m sestamibi excretion from the liver is mediated by P-glycoprotein, and inhibition of P-glycoprotein transport not only delays liver excretion but also increases the liver uptake of Tc-99m sestamibi. Because this observation deserves further investigation, the inhibition of P-glycoprotein function with nontoxic multidrug-resistance reversing agents may be used as an intervention to increase the tumor uptake of Tc-99m sestamibi and to increase the sensitivity of Tc-99m sestamibi tumor imaging.
癌症患者无法治愈主要是由于P -糖蛋白过度表达导致耐药性的产生。已鉴定出多种药物，包括环孢素A，它可通过抑制P -糖蛋白转运来逆转耐药性。锝- 99m甲氧基异丁基异腈是P -糖蛋白的一种底物。P -糖蛋白通常表达于肝细胞的胆小管表面，负责肝脏中阳离子代谢产物的排泄。本研究的目的是评估环孢素A对锝- 99m甲氧基异丁基异腈在体内生物分布的影响。
选择5例脱发患者和2例接受环孢素A治疗的肾移植患者进行研究。所有患者在服用环孢素A之前及之后至少2周进行检查。在注射后5、30、60、120和180分钟获取腹部平面图像，进行锝- 99m甲氧基异丁基异腈闪烁扫描，并计算肝心比。
获取了所有患者的血浆环孢素A、胆红素水平、肝酶及肌酐清除率值。其中3例患者血浆环孢素A水平升至400 pg/dl以上。服用环孢素A后肝心比显著升高（P < 0.01）。服用环孢素A后，锝- 9m甲氧基异丁基异腈排泄延迟，肝脏摄取增加。5分钟时差异为17%，180分钟时为38%。环孢素A毒性患者肝脏滞留最为明显。
本研究虽患者数量有限，但表明肝脏中锝- 99m甲氧基异丁基异腈的排泄由P -糖蛋白介导，抑制P -糖蛋白转运不仅会延迟肝脏排泄，还会增加肝脏对锝- 99m甲氧基异丁基异腈的摄取。鉴于这一观察结果值得进一步研究，使用无毒的多药耐药逆转剂抑制P -糖蛋白功能，可能作为一种干预措施来增加锝- 99m甲氧基异丁基异腈在肿瘤中的摄取，并提高锝- 99m甲氧基异丁基异腈肿瘤显像的敏感性。
