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.

• Authors: Emiko Asakura, Hironao Nakayama, Masami Sugie, Ying Lan Zhao, Masayuki Nadai, Kiyoyuki Kitaichi, Akemi Shimizu, Mika Miyoshi, Kenji Takagi, Kenzo Takagi, Takaaki Hasegawa
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 484 Issue 2-3 Pg. 333-9 (Jan 26 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 14744620 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Doxorubicin
• Azithromycin

Topics

• Animals
• Antibiotics, Antineoplastic (metabolism)
• Azithromycin (pharmacology)
• Bile (drug effects, metabolism)
• Bile Ducts (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Doxorubicin (antagonists & inhibitors, metabolism)
• Drug Resistance, Neoplasm (drug effects, physiology)
• Humans
• Intracellular Fluid (drug effects, metabolism)
• K562 Cells
• Liver (drug effects, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley