Dexamethasone changes the disposition of atorvastatin by targeting the
LXRα-OATP1B1 pathway
Abstract
Chronic subdural hematoma (CSDH) is one of the most common neurological
disorders. In recent years, atorvastatin (ATV) combined with
dexamethasone (DXM) has been proved to be a more efficacious therapy in
treating patients with CSDH than ATV monotherapy. To investigate whether
DXM has an effect on the pharmacokinetics of ATV, the expression of
organic anion transport polypeptides 1B1 (OATP1B1) and upstream nuclear
receptors liver X receptor α (LXRα) in rat liver and HepG2 cells were
evaluated. The results showed that when DXM was combined with ATV, the
area under curve (AUC(0~∞)) of ATV, o-ATV and p-ATV was
increased by 1.550, 1.420, 1.676 times, respectively. In HepG2 cells,
DXM inhibited the uptake of ATV by 59.24%. Also, DXM decreased the
expression of OATP1B1 and LXRα both in the rat liver and HepG2 cells.
Dual-luciferase reporter assay indicated that DXM had an inhibitory
effect on the LXRα-OATP1B1 pathway. In conclusion, DXM downregulated the
protein expression of OATP1B1 by inhibiting the LXRα-OATP1B1 pathway,
thus, decreasing hepatic drug uptake and increasing plasma concentration
of ATV and its active metabolites.