Purpose: 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.
Methods: 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.
Results: 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.
Conclusions: 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.