Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

“…In our study, a comparison of clinical characteristics between ADR and non-ADR groups (Table 1) showed that these risk factors do not appear to confound the genetic influence of the NR1I3 rs2307424 polymorphism, because frequencies in the groups were similar. With exception of calcium channel blocker use, that was more frequent in non-ADR group than in ADR patients, however, these drugs are classical CYP3A4 and glycoprotein P inhibitors, and might increase risk of adverse drug reaction (28)(29)(30). To the best of our knowledge, only one previous study (31) investigated the association of PPARA rs1800206 polymorphism with the lipid-lowering efficacy of statins; they found no association between PPARA rs1800206 genotypes and lipid baseline levels or lipid-lowering response to fluvastatin.…”

Interaction between Amlodipine and Simvastatin in Patients with Hypercholesterolemia and Hypertension

“…In this study, we measured the total HMG-CoA reductase inhibitory activity resulting from simvastatin acid and all other active acid metabolites of simvastatin, since this level is believed to be relevant to the systemic adverse effects for this class of agents (35). The pharmacokinetics of simvastatin has been shown to be affected by potent CYP3A4 inhibitors (13)(14)(15)18). Amlodipine, which is metabolized by CYP3A4, has been reported to show inhibitory effects on CYP3A4 in vitro (31).…”

“…The pharmacokinetics of simvastatin has been reported to be affected by potent CYP3A4 inhibitors such as itraconazole (13), erythromycin (14), verapamil (14) and nelfinavir (15). Moreover, we have previously reported that diltiazem, which is a selective inhibitor of CYP3A4 (16,17), caused a 2-fold increase of the area under the concentrationtime curve (AUC) of HMG-CoA reductase inhibitors (18).…”

The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes

“…) and ABCB1 (Yamasaki et al 2009) expression levels in vitro, and that this effect may extend to in vivo (Watanabe et al 2004), suggesting that statins may act as perpetrators for drug-drug interactions as well as victims. Such interactions are presumed to occur through the activation of members of the nuclear receptor superfamily, which act as ligand-activated transcription factors regulating many aspects 6 of cellular metabolism (Plant and Aouabdi 2009).…”