Possible involvement of P-glycoprotein in the biliary excretion of grepafloxacin.
1. In the present study, we have examined the effects of the quinolones norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), tosufloxacin (TFLX), lomefloxacin (LFLX), sparfloxacin (SPFX) and grepafloxacin (GPFX) on the efflux of doxorubicin from mouse leukaemia P388/ADR cells expressing P-glycoprotein. The relationship between their partition coefficients (hydrophobicity) and effluxing potencies was also elucidated. 2. Both TFLX and SPFX strongly increased the intracellular accumulation of doxorubicin (5 micromol/L) in P388/ADR cells, but had no effect on P388/S cells not expressing P-glycoprotein. The rank of order of the potency of the quinolones (TFLX > SPFX > GPFX > NFLX) was not related directly to their hydrophobicity. These results suggest that some quinolones can reverse anticancer drug resistance. 3. Because GPFX is more highly excreted into the bile than other known quinolones, the effects of doxorubicin (10 mg/kg) or the well-known inhibitors of P-glycoprotein, namely cyclosporine A (10 mg/kg) and erythromycin (100 mg/kg), on the biliary excretion of GPFX at steady state was studied in rats. 4. Doxorubicin, cyclosporine A and erythromycin significantly decreased the biliary clearance of GPFX. Cyclosporine A and erythromycin had a much stronger inhibitory effect on the biliary excretion of GPFX than doxorubicin. These results suggest the possibility that GPFX is, at least in part, excreted into the bile by a P-glycoprotein-mediated transport mechanism.
Zhao
Ying Lan
YL
Department of Medical Technology, Nagoya University School of Health Sciences, Meijo University, Nagoya, Japan.
Cai
Shao Hui
SH
Wang
Li
L
Kitaichi
Kiyoyuki
K
Tatsumi
Yasuaki
Y
Nadai
Masayuki
M
Yoshizumi
Hideo
H
Takagi
Kenji
K
Takagi
Kenzo
K
Hasegawa
Takaaki
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001646:Bile / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D024841:Fluoroquinolones; D007941:Leukemia P388; D008297:Male; D051379:Mice; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D010879:Piperazines; D015363:Quinolones; D004317:Doxorubicin; C075375:grepafloxacin