The effect of P-glycoprotein function inhibition with cyclosporine A on the biodistribution of Tc-99m sestamibi

Purpose: The failure to cure persons with cancer is caused primarily by the development of drug resistance by overexpression of p-glycoprotein. Divers e groups of drugs have been identified, including cyclosporine A, which can reverse drug resistance by inhibiting P-glycoprotein transport. Tc-99m ses tamibi is a substrate for P-glycoprotein. P-glycoprotein is normally expres sed in biliary canalicular surfaces of hepatocytes and is responsible for t he excretion of cationic metabolites from the liver. The aim of the current study was to evaluate the effect of cyclosporine A on the biological distr ibution 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 cyclospor ine A. Tc-99m sestamibi scintigraphy was performed by obtaining planar abdo minal images at 5, 30, 60, 120, and 180 minutes after injection, and the li ver-heart ratios were calculated. Results: Plasma cyclosporine A, bilirubin levels, liver enzymes, and creati nine 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% a t 5 minutes and 38% at 180 minutes. Liver retention was greatest in patient s 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 observati on deserves further investigation, the inhibition of P-glycoprotein functio n with nontoxic multidrug-resistance reversing agents may be used as an int ervention to increase the tumor uptake of Tc-99m sestamibi and to increase the sensitivity of Tc-99m sestamibi tumor imaging.