INHIBITION OF INTESTINAL P-GLYCOPROTEIN AND EFFECTS ON ETOPOSIDE ABSORPTION

P-glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance . Pgp is also expressed at the brush-border membrane of the small inte stine under normal physiological conditions. We hypothesized that inhi bition of intestinal Pgp might decrease the efflux of etoposide from t he blood into the intestinal lumen, thereby, increasing the bioavailab ility of etoposide. The absorption of etoposide was studied using ever ted gut sacs prepared from rat jejunum and ileum. The addition of C219 , a monoclonal antibody of Pgp, at 100 ng/ml or of 0.2 M 5'-adenylylim idodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic ag ent, has been demonstrated to circumvent multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac increased the absorption of etoposide. In vivo absorption of etoposide was also studied by intraluminal perfu sion of the drug in the small intestine of anesthetized rats. Intraven ous infusion of quinidine at either 1 or 2 mg/h increased the serum le vel of etoposide in a dose-dependent manner. Intravenous infusion of e toposide at 0.2 mg/h resulted in luminal exsorption of the drug in the small intestine. The intestinal clearance of etoposide was 41.7 +/- 7 .2 mi kg(-1), which decreased to 18.4 +/- 3.9 ml kg(-1) with the infus ion of quinidine at 1 mg/h. The present data confirm that intestinal P gp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposid e.