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Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats.

Abstract：

:The present study aims to investigate whether azithromycin reverses P-glycoprotein-dependent anticancer drug resistance in vitro and modifies the hepatobiliary excretion of doxorubicin, a substrate for P-glycoprotein in vivo. Azithromycin increased dose-dependently the intracellular accumulation of doxorubicin in adriamycin-resistant human myelogenous leukemia cells (K562/ADR) with no effect on the expression of P-glycoprotein in the cells. However, the inhibitory effect was much weaker than that of cyclosporin A and was comparable to that of erythromycin. When Sprague-Dawley (SD) rats, which have drug transporting P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) in the bile canalicular membrane of hepatocytes, received an infusion of doxorubicin, the steady-state biliary clearance of doxorubicin was significantly decreased for 40 min after a single intravenous injection of azithromycin. However, azithromycin did not increase the plasma concentration of doxorubicin. The biliary clearance of doxorubicin in Eisai hyperbilirubinemic rats (EHBRs), which have a hereditary deficiency in Mrp2, was significantly decreased compared with that in Sprague-Dawley rats, suggesting the involvement of Mrp2 in the biliary excretion of doxorubicin. The present findings suggest that azithromycin overcomes P-glycoprotein-dependent anticancer drug resistance of tumors by inhibiting the binding of doxorubicin to P-glycoprotein in K562/ADR cells and inhibits the hepatobiliary excretion of drugs that are substrates for P-glycoprotein and Mrp2.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Asakura E,Nakayama H,Sugie M,Zhao YL,Nadai M,Kitaichi K,Shimizu A,Miyoshi M,Takagi K,Takagi K,Hasegawa T

doi

10.1016/j.ejphar.2003.11.035

keywords:

subject

Has Abstract

pub_date

2004-01-26 00:00:00

pages

333-9

issue

2-3

eissn

0014-2999

issn

1879-0712

pii

S0014299903026803

journal_volume

484

pub_type

杂志文章

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