Interaction of docetaxel ("Taxotere") with human P-glycoprotein.
The interaction of docetaxel ("Taxotere") with P-glycoprotein (P-gp) was examined using porcine kidney epithelial LLC-PK1 and LLC-GA5-COL150 cells, overexpressing human P-gp selectively on the apical plasma membrane by transfection of human MDR1 cDNA into the LLC-PK1 cells. The basal-to-apical transport of [14C]docetaxel in LLC-GA5-COL150 cells significantly exceeded that in LLC-PK1 cells, but the apical-to-basal transport was decreased in LLC-GA5-COL150 cells. The intracellular accumulation after its basal or apical application to LLC-GA5-COL150 cells was 4- to 20-fold lower than that of LLC-PK1 cells. Multidrug resistance (MDR) modulators, i.e., cyclosporin A and SDZ PSC 833, inhibited the basal-to-apical transport and increased the apical-to-basal transport of [14C]docetaxel in LLC-GA5-COL150 cells, but verapamil affected only apical-to-basal transport. The intracellular accumulation after basal or apical application to LLC-GA5-COL150 cells was also increased by these three MDR modulators. These observations demonstrated that docetaxel is a substrate for human P-gp, suggesting that docetaxel-drug interactions occur via P-gp. The inhibition of [14C]docetaxel transport by the MDR modulators, as well as daunorubicin and vinblastine, was also found in LLC-PK1 cells, which endogenously express P-gp at lower levels, and concentrations showing similar levels of inhibition were lower than those in the case of LLC-GA5-COL150 cells. These observations indicate that it is necessary to consider the pharmacokinetic and pharmacodynamic interactions of docetaxel via P-gp.
Shirakawa
K
K
Second Department of Internal Medicine, School of Medicine, Kobe University.
Takara
K
K
Tanigawara
Y
Y
Aoyama
N
N
Kasuga
M
M
Komada
F
F
Sakaeda
T
T
Okumura
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013552:Swine; D043823:Taxoids; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel