Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats.
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.
Asakura
Emiko
E
Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi, Nagoya 461-8673, Japan.
Nakayama
Hironao
H
Sugie
Masami
M
Zhao
Ying Lan
YL
Nadai
Masayuki
M
Kitaichi
Kiyoyuki
K
Shimizu
Akemi
A
Miyoshi
Mika
M
Takagi
Kenji
K
Takagi
Kenzo
K
Hasegawa
Takaaki
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D017963:Azithromycin / Q000494:pharmacology*; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D020014:K562 Cells; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D017963:Azithromycin