Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin.
OBJECTIVE
In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions.


METHODS
P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 microM.


RESULTS
Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 -25-50 microM) but SVA not showing any inhibition of P-gp.


CONCLUSIONS
The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.
Hochman
Jerome H
JH
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. Jerome_Hochman@merck.com
Pudvah
Nicole
N
Qiu
Julia
J
Yamazaki
Masayo
M
Tang
Cuyue
C
Lin
Jiunn H
JH
Prueksaritanont
Thomayant
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000069059:Atorvastatin; D001693:Biological Transport, Active; D002460:Cell Line; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology; D019438:Ritonavir / Q000378:metabolism; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D011758:Pyrroles; C063287:simvastatin acid; D000069059:Atorvastatin; D019821:Simvastatin; D019438:Ritonavir