Effect of ketoconazole on the transport and metabolism of drugs in the human liver cell model


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Abstract

The effect of ketoconazole on the biotransformation of amiodarone, rosiglitazone, and cyclophosphamide was studied using the human liver cell model based on differentiated HepaRG spheroids. The concentrations of major metabolites of amiodarone and cyclophosphamide were found to decrease in the presence of ketoconazole, a cytochrome P450 3A4 inhibitor. The concentration of the major metabolite of rosiglitazone, N-desmethyl rosiglitazone, decreased upon the addition of either sulfaphenazole, a cytochrome P450 2C9 inhibitor, or ketoconazole. The rosiglitazone metabolism involves CYP2C9 and CYP2C19. This result is attributable to the inhibitory effect of ketoconazole on p-glycoprotein, which decreases N-desmethyl rosiglitazone concentration in the culture medium. The utilization of the human liver cell model and selective inhibitors of transporters and cytochrome P450 isoforms can serve for standardization of the studies of drug-drug interactions involved in drug transport and metabolism.

About the authors

S. V. Nikulin

LLC BioClinicum Research and Development Center

Email: andrey.poloznikov@gmail.com
Russian Federation, 85 Build., 2 ul. Ugreshskaya, Moscow, 115088

E. A. Tonevitsky

Department of Chemistry, M. V. Lomonosov Moscow State University

Email: andrey.poloznikov@gmail.com
Russian Federation, Build. 3, 1 Leninskie Gory, Moscow, 119992

A. A. Poloznikov

LLC BioClinicum Research and Development Center

Author for correspondence.
Email: andrey.poloznikov@gmail.com
Russian Federation, 85 Build., 2 ul. Ugreshskaya, Moscow, 115088

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