[Effect of S9788, cyclosporin A and verapamil on intracellular accumulation of doxorubicin, daunorubicin and daunorubicinol in primary rat hepatocyte culture].
The aim of this study was to compare the effect of three MDR modulators, cyclosporine A, S9788 and verapamil on the efflux of two anthracyclines, doxorubicin and daunorubicin and of daunorubicinol, the C-13 alcohol metabolite of daunorubicin. Rat hepatocyte primary cultures were used as a model of P-gp expression. They allow to study MDR at different levels of P-gp expression which increases in parallel with culture time. Furthermore, hepatocytes are able to metabolize drugs and enable determination of the role of P-gp on metabolite efflux. Hepatocytes grown for 4 or 48 hours were incubated for 6 hours in the presence of a combination of each modulator and one of the two anthracyclines (0.5 microM). Modulator concentrations used were 1, 5 and 15 microM when associated with DOX, and 1 and 15 when associated with DNR. In fresh hepatocytes, the three MDR modulators did not induce an increase in intracellular retention of the two anthracyclines compared to controls without MDR modulators. At 48 hours of culture, the three tested drugs increased intracellular accumulation of DOX. However, daunorubicin retention was not modified but that of its metabolite was increased. The activity rank order was cyclosporine A > S9788 > verapamil. Cyclosporine A and S9788 were active in simultaneous as well as in sequential combinations with anthracyclines. Verapamil was only effective when co-incubated with anthracyclines.
Le Bot
M A
MA
Service de pharmacologie, CHU, Brest.
Kernaleguen
D
D
Simon
I
I
Berlion
M
M
Riché
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000032:analysis*; D004317:Doxorubicin / Q000032:analysis*; D018432:Drug Resistance, Multiple; D008099:Liver / Q000737:chemistry / Q000166:cytology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010880:Piperidines; D014227:Triazines; C077022:S 9788; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C000847:daunorubicinol; D003630:Daunorubicin
Effet du S9788, de la ciclosporine A et du vérapamil sur l'accumulation intracellulaire de la doxorubicine, de la daunorubicine et du daunorubicinol dans des hépatocytes de rat en culture primaire.