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

Emiko Asakura, Hironao Nakayama, Masami Sugie, Ying Lan Zhao, Masayuki Nadai, Kiyoyuki Kitaichi, Akemi Shimizu, Mika Miyoshi, Kenji Takagi, Kenzo Takagi, Takaaki Hasegawa

Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi, Nagoya 461-8673, Japan.

European journal of pharmacology 2004 Jan 26

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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 cell s (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.

Citation

Emiko Asakura, Hironao Nakayama, Masami Sugie, Ying Lan Zhao, Masayuki Nadai, Kiyoyuki Kitaichi, Akemi Shimizu, Mika Miyoshi, Kenji Takagi, Kenzo Takagi, Takaaki Hasegawa. Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats. European journal of pharmacology. 2004 Jan 26;484(2-3):333-9