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 intestine under normal physiological conditions. We hypothesized that inhibition of intestinal Pgp might decrease the efflux of etoposide from the blood into the intestinal lumen, thereby, increasing the bioavailability of etoposide. The absorption of etoposide was studied using everted 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'-adenylylimidodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic agent, 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 perfusion of the drug in the small intestine of anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/h increased the serum level of etoposide in a dose-dependent manner. Intravenous infusion of etoposide 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 ml kg-1, which decreased to 18.4 +/- 3.9 ml kg-1 with the infusion of quinidine at 1 mg/h. The present data confirm that intestinal Pgp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposide.
Leu
B L
BL
Department of Pharmacology, National Cheng Kung University, Medical College, Tainan, Taiwan, Republic of China.
Huang
J D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000266:Adenylyl Imidodiphosphate; D005047:Etoposide; D011802:Quinidine