Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein.

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Kusunoki N, Takara K, Tanigawara Y, Yamauchi A, Ueda K, Komada F, Ku Y, Kuroda Y, Saitoh Y, Okumura K

Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein.

Jpn J Cancer Res. 1998 Nov;89(11):1220-8.

PubMed ID

9914792 [ View in PubMed

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Abstract

The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 microM, respectively, and those for vinblastine transport were 1.06 and 5.10 microM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Doxorubicin	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Cyclosporine	P-glycoprotein 1	IC 50 (nM)	3660	N/A	N/A	Details