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Publications (4)17.89 Total impact

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    ABSTRACT: Novel potential inhibitors of the postsqualene portion of cholesterol synthesis were screened in HepG2 cells. 2-(4-Phenethylpiperazin-1-yl)-1-(pyridine-3-yl)ethanol (LK-980) was identified as a prospective compound and was characterized further in cultures of human primary hepatocytes from seven donors. In vitro kinetic measurements show that the half-life of LK-980 is at least 4.3 h. LK-980 does not induce CYP3A4 mRNA nor enzyme activity. Target prediction was performed by gas chromatography-mass spectrometry, allowing simultaneous separation and quantification of nine late cholesterol intermediates. Experiments indicated that human sterol Δ(7)-reductase (DHCR7) is the major target of LK-980 (34-fold increase of 7-dehydrocholesterol), whereas human sterol Δ(14)-reductase (DHCR14), human sterol Δ(24)-reductase (DHCR24), and human sterol C5-desaturase (SC5DL) represent minor targets. In the absence of purified enzymes, we used the mathematical model of cholesterol synthesis to evaluate whether indeed more than a single enzyme is inhibited. In silico inhibition of only DHCR7 modifies the flux of cholesterol intermediates, resulting in a sterol profile that does not support experimental data. Partial inhibition of the DHCR14, DHCR24, and SC5DL steps, in addition to DHCR7, supports the experimental sterol profile. In conclusion, we provide experimental and computational evidence that LK-980, a novel inhibitor from the late portion of cholesterol synthesis, inhibits primarily DHCR7 and to a lesser extent three other enzymes from this pathway.
    Drug metabolism and disposition: the biological fate of chemicals 10/2010; 39(1):39-46. DOI:10.1124/dmd.110.035840 · 3.74 Impact Factor
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    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 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.
    Drug metabolism and disposition: the biological fate of chemicals 11/2008; 37(2):375-85. DOI:10.1124/dmd.108.023887 · 3.74 Impact Factor
  • Journal of Hepatology 01/2008; 48. DOI:10.1016/S0168-8278(08)60236-6 · 10.40 Impact Factor
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    ABSTRACT: Success of organ transplantation and increasing graft and recipient survival is partly due to the improvement of immunosuppressive therapy. Cyclosporine A (CYA) widely used in liver or kidney transplantation selectively suppresses T-cell immunity. Therapeutic drug monitoring of CYA is essential because of the narrow therapeutic window and high interindividual variety in bioavailability, metabolism and elimination of CYA. Immunoassay techniques (FPIA, EMIT) offer simple and high throughput determination of CYA blood concentrations; however, the accuracy highly depends on the selectivity of the antibodies used in immunoassay procedures. Some of CYA-metabolites cross-react with the antibodies of immunoassays, which lead to false results of CYA concentration. An analytical system using two-dimension chromatography in combination with tandem mass spectrometry (HPLC-MS/MS) was developed for the measurements of blood concentrations of CYA and some of its hydroxylated metabolites, which may contribute to the toxicity of the parent compound. The association between CYA metabolites and liver function parameters (alkaline phosphatase, γ-glutamyltransferase, transaminases: GOT, GPT and serum bilirubin) was also investigated in liver transplants (n=51). The concentration of 1,9-dihydroxy-CYA showed strong correlation with γ-glutamyltransferase and serum bilirubin levels. Additionally, the alterations in 1,9-dihydroxy-CYA concentrations seemed to cause parallel changes of these parameters. The immunosuppressive therapy for the patients with continuously increased levels of 1,9-dihydroxy-CYA was modified. Replacement of CYA to tacrolimus resulted in the elimination of 1,9-dihydroxy-CYA and normalization of γ-glutamyltransferase and serum bilirubin levels. Although our HPLC-MS/MS method is not considered to be applicable for high throughput screening of CYA blood levels, but may provide information on the alterations in CYA metabolism and may lead to the optimization of immunosuppressive therapy.
    10th European Regional International society for the study of xenobiotics Meeting;