Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells.

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Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, Dvorak Z

Dual effects of ketoconazole cis-enantiomers on CYP3A4 in human hepatocytes and HepG2 Cells.

PLoS One. 2014 Oct 24;9(10):e111286. doi: 10.1371/journal.pone.0111286. eCollection 2014.

PubMed ID

25343516 [ View in PubMed

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Abstract

Antifungal drug ketoconazole causes severe drug-drug interactions by influencing gene expression and catalytic activity of major drug-metabolizing enzyme cytochrome P450 CYP3A4. Ketoconazole is administered in the form of racemic mixture of two cis-enantiomers, i.e. (+)-ketoconazole and (-)-ketoconazole. Many enantiopure drugs were introduced to human pharmacotherapy in last two decades. In the current paper, we have examined the effects of ketoconazole cis-enantiomers on the expression of CYP3A4 in human hepatocytes and HepG2 cells and on catalytic activity of CYP3A4 in human liver microsomes. We show that both ketoconazole enantiomers induce CYP3A4 mRNA and protein in human hepatocytes and HepG2 cells. Gene reporter assays revealed partial agonist activity of ketoconazole enantiomers towards pregnane X receptor PXR. Catalytic activity of CYP3A4/5 towards two prototypic substrates of CYP3A enzymes, testosterone and midazolam, was determined in presence of both (+)-ketoconazole and (-)-ketoconazole in human liver microsomes. Overall, both ketoconazole cis-enantiomers induced CYP3A4 in human cells and inhibited CYP3A4 in human liver microsomes. While interaction of ketoconazole with PXR and induction of CYP3A4 did not display enantiospecific pattern, inhibition of CYP3A4 catalytic activity by ketoconazole differed for ketoconazole cis-enantiomers ((+)-ketoconazole IC(5)(0) 1.69 microM, Ki 0.92 microM for testosterone, IC(5)(0) 1.46 microM, Ki 2.52 microM for midazolam; (-)-ketoconazole IC(5)(0) 0.90 microM, Ki 0.17 microM for testosterone, IC(5)(0) 1.04 microM, Ki 1.51 microM for midazolam).

DrugBank Data that Cites this Article

Drugs

Levoketoconazole

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Levoketoconazole	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor Inducer	Details
Levoketoconazole	Cytochrome P450 3A5	Protein	Humans	No	Inhibitor Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Ketoconazole	Approved Investigational	CYP3A4	1576	upregulated	Ketoconazole results in increased expression of CYP3A4 mRNA	7q22.1