Drug interaction potential of 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3-yl)ethanol (LK-935), the novel nonstatin-type cholesterol-lowering agent.
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 14alpha-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.
Monostory
Katalin
K
Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary. monostor@chemres.hu
Pascussi
Jean-Marc
JM
Szabó
Pál
P
Temesvári
Manna
M
Köhalmy
Krisztina
K
Acimovic
Jure
J
Kocjan
Darko
D
Kuzman
Drago
D
Wilzewski
Britta
B
Bernhardt
Rita
R
Kóbori
László
L
Rozman
Damjana
D
D000924:Anticholesteremic Agents / Q000378:metabolism / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology
D000924:Anticholesteremic Agents; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D000069059:Atorvastatin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human