Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice.
The aim of this study was to characterise the role of the efflux transporter P-glycoprotein in the disposition of cerivastatin. We investigated directional transport characteristics of [14C]cerivastatin across cell monolayers expressing P-glycoprotein (Caco-2 and L-MDR1) and disposition of cerivastatin in mice with disrupted mdr1a and mdr1b genes. The mice were given orally 1 mg/kg cerivastatin and plasma and tissue samples for analysis of cerivastatin were obtained 10, 20, or 30 min after drug administration. Four knock-out mice and four wild-type mice were studied at each time point. In addition, the hypothesis that gemfibrozil-mediated inhibition of P-glycoprotein contributes to the interaction between gemfibrozil and cerivastatin was tested in Caco-2 cells. The apparent permeability coefficient (P(app)) value for the basal-to-apical transport of cerivastatin in Caco-2 and L-MDR1 cell monolayers was 2.4 times (P<0.001) and 3.8 times (P<0.001) as high as the apical-to-basal P(app) value respectively. The P-glycoprotein inhibitor PSC-833 (1 microM) inhibited the net basal-to-apical transport of cerivastatin in Caco-2 monolayers by 35% (P<0.01) and the MRP inhibitor MK-571 (10 microM) by 50% (P<0.01). At concentrations up to 250 microM, gemfibrozil showed no significant effects on the net transport of cerivastatin in Caco-2 cells. The concentration of cerivastatin in the brain at 30 min was 3.1 times higher in the knock-out mice than in the wild-type mice (P<0.05). The brain-to-plasma cerivastatin concentration ratio at 20 min and 30 min was 2.1 (P<0.05) and 3.6 times (P<0.05) higher respectively in the knock-out animals compared with the wild-type animals. Collectively, these results indicate that cerivastatin is a P-glycoprotein substrate, although other transporters probably contribute to cerivastatin transport in humans. As several statins are P-glycoprotein substrates, beneficial as well as adverse effects of the statins might be affected by interindividual differences in P-glycoprotein expression or function caused by, e.g., the MDR1 polymorphism.
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. kari.kivisto@ikp-stuttgart.de
Kari T
KT
Kivistö
Jörg
J
Zukunft
Ute
U
Hofmann
Mikko
M
Niemi
Sabine
S
Rekersbrink
Swetlana
S
Schneider
Gerd
G
Luippold
Matthias
M
Schwab
Michel
M
Eichelbaum
Martin F
MF
Fromm
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004347:Drug Interactions; D015248:Gemfibrozil / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D015248:Gemfibrozil; D000960:Hypolipidemic Agents; D011725:Pyridines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C086276:cerivastatin