Drug Interaction Potential of 2-((3,4-Dichlorophenethyl)(propyl)amino)-1-(pyridin-3-yl)ethanol (LK-935), the Novel Nonstatin-Type Cholesterol-Lowering Agent

Abstract

ABSTRACT:The widely prescribed lipid-lowering statins are considered to be relatively safe drugs. However, the risk of severe myopathy and drug interactions as a consequence of statin therapy provides a challenge for development of novel cholesterol-lowering agents, targeting enzymes other than HMG-CoA reductase. The novel pyridylethanol-(phenylethyl)amine derivative, (2-((3,4-dichlorophenethyl)(propyl)-amino)-1-(pyridin-3-yl)ethanol (LK-935), blocking lanosterol 14␣-demethylase, was demonstrated to efficiently reduce cholesterol biosynthesis. The drug interaction potential of LK-935 was investigated and compared with that of atorvastatin and rosuvastatin in primary human hepatocytes. Clear evidence was provided for the induction of CYP3A4 by LK-935. LK-935 was proved to be a potent human pregnane X receptor (hPXR) activator as a prerequisite for the transcriptional activation of CYP3A4 gene; however, the rapid metabolism of LK-935 in primary hepatocytes prevented maximal CYP3A4 induction. Therefore, the induction of CYP3A4 by LK-935 may be prone to mild or negligible drug interactions. However, because CYP3A4 and also CYP2C9 play a significant role in LK-935 metabolism, the inhibition of these cytochromes P450 by coadministered drugs may lead to some increase in the LK-935 concentration required for the potent induction of CYP3A4. Rosuvastatin was found to increase human constitutive androstane receptor (hCAR)-mediated transcription of CYP3A4, CYP2C9, and CYP2B6 genes, predicting the consequent potential for drug interactions with several coadministered drugs. Activation of hCAR and hPXR by atorvastatin and the subsequent induction of not only CYP2B6 and CYP3A4 but also of CYP2C9 present an additional target by which atorvastatin, a widely used cholesterol-lowering drug, can modify the kinetics of numerous drugs.

Atorvastatin Treatment Induces Uptake and Efflux Transporters in Human Liver

“…No upregulation of CYP2C9 or CYP3A4 occurred in the statin-treated subjects, in contrast to previously in vitro studies showing that atorvastatin upregulates cytochrome enzymes in primary hepatocytes (Kocarek et al, 2002;Monostory et al, 2009). However, in these experiments, very high statin concentrations (10-30 mM) were used, compared with concentrations of 1-10 nM achieved in human serum during statin treatment (Bjorkhem-Bergman et al, 2011).…”

Effects of atorvastatin metabolites on induction of drug‐metabolizing enzymes and membrane transporters through human pregnane X receptor

“…Atorvastatin induces the expression of CYP2B6, CYP2C8, CYP2C9 and CYP3A4 mRNA, protein and enzymic activity in hepatocytes (Kocarek et al ., 2002; Feidt et al ., 2010) and activates human PXR and CAR in reporter gene assays (Kobayashi et al ., 2005; Monostory et al ., 2009; Yamasaki et al., 2009), thereby suggesting ligand binding to these xenosensing nuclear receptors as the molecular mechanism of induction. It was the aim of this study to elucidate this hypothesis and to analyse any potential role of atorvastatin metabolites in induction.…”

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

“…M4a and M4b were formed from M2 via further hydroxylation at the propyl group. Like atorvastatin and rosuvastatin, LK-935 was an inducer of CYP3A4 through transactivation of nuclear receptors in human hepatocytes [1043]. However, LK-935 did not induce CYP2C9 and 2B6 which were significantly induced by atorvastatin and rosuvastatin.…”

“…CYP2C9 and CYP3A4 are the predominant enzymes involved in the Ndealkylation and hydroxylation of LK-935, yielding M1, M2, M3a, M3b, and two minor metabolites M4a and M4b (Fig. (128)) [1043]. M1 resulted from the cleavage of the propyl group from the tertiary amine; while the hydroxylation of M3b on the pyridine ring was catalyzed by CYP2C9 and 3A4.…”