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.
Similar content being viewed by others
References
S.-M. Huang, J. M. Strong, L. Zhang, K. S. Reynolds, S. Nallani, R. Temple, S. Abraham, S. Al Habet, R. K. Baweja, G. J. Burckart, S. Chung, P. Colangelo, D. Frucht, M. D. Green, P. Hepp, E. Karnaukhova, H.-S. Ko, J.-I. Lee, P. J. Marroum, J. M. Norden, W. Qiu, A. Rahman, S. Sobel, T. Stifano, K. Thummel, X.-X. Wei, S. Yasuda, J. H. Zheng, H. Zhao, L. J. Lesko, J. Clin, Pharmacol., 2008, 48,662.
P. J. McDonnell, M. R. Jacobs, Ann. Pharmacother., 2002, 36, 1331.
J. A. Williams, R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup, S. E. Ball, Drug Metab. Dispos., 2004, 32, 1201.
C. Giraud, A. Tran, E. Rey, J. Vincent, J.-M. Tréluyer, G. Pons, Drug Metab. Dispos., 2004, 32, 1279.
Guidance for Industry, Drug Interaction Studies–study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Silver Spring, 2012.
Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv [Guidelines for Preclinical Trials of Pharmaceutical Agents], Ed. A. N. Mironov, Grif i K, Moscow, 2012 (in Russian).
J. H. Lin, M. Yamazaki, Clin. Pharmacokinet., 2003, 42,59.
S. R. Faucette, R. L. Hawke, S. S. Shord, E. L. Lecluyse, C. M. Lindley, Drug Metab. Dispos., 2001, 29, 1123.
M. A. Gibbs, K. E. Thummel, D. D. Shen, K. L. Kunze, Drug Metab. Dispos., 1999, 27,180.
Y. Sai, R. Dai, T. J. Yang, K. W. Krausz, F. J. Gonzalez, H. V. Gelboin, M. Shou, Xenobiotica, 2000, 30,327.
S. J. Baldwin, J. C. Bloomer, G. J. Smith, A. D. Ayrton, S. E. Clarke, R. J. Chenery, Xenobiotica, 1995, 25,261.
S. S. Bun, J. Ciccolini, H. Bun, C. Aubert, J. Catalin, J. Chemother., 2003, 15,266.
C. Emoto, S. Murase, Y. Sawada, B. C. Jones, K. Iwasaki, Drug Metab. Pharmacokinet., 2003, 18,287.
V. Kumar, D. A. Rock, C. J. Warren, T. S. Tracy, J. L. Wahlstrom, Drug Metab. Dispos., 2006, 34, 1903.
B. B. Rasmussen, T. L. Nielsen, K. Brøsen, Pharmacol. Toxicol., 1998, 83,240.
E. J. Wang, K. Lew, C. N. Casciano, R. P. Clement, W. W. Johnson, Antimicrob. Agents Chemother., 2002, 46,160.
J. L. Lam, L. Z. Benet, Drug Metab. Dispos., 2004, 32, 1311.
A. V. Aleksandrova, N. V. Pul´kova, D. A. Sakharov, Byul. Eksperim. Biol. Med. [Bull. Exp. Biol. Med.], 2016, 161, 60 (in Russian).
E.-M. Materne, A. P. Ramme, A. P. Terrasso, M. Serra, P. M. Alves, C. Brito, D. A. Sakharov, A. G. Tonevitsky, R. Lauster, U. Marx, J. Biotechnol., 2015, 205,36.
G. Langley, C. P. Austin, A. K. Balapure, L. S. Birnbaum, J. R. Bucher, J. Fentem, S. C. Fitzpatrick, J. R. Fowle, R. J. Kavlock, H. Kitano, B. A. Lidbury, A. R. Muotri, S.-Q. Peng, D. Sakharov, T. Seidle, T. Trez, A. Tonevitsky, A. van de Stolpe, M. Whelan, C. Willett, Environ. Health Perspect., 2015, 123, A268.
E.-M. Materne, A. G. Tonevitsky, U. Marx, Lab. Chip., 2013, 13, 3481.
A. V. Aleksandrova, O. A. Burmistrova, K. A. Fomicheva, D. A. Sakharov, Byul. Eksperim. Biol. Med. [Bull. Exp. Biol. Med.], 2016, 161, 138 (in Russian).
D. V. Maltseva, N. A. Khaustova, N. N. Fedotov, E. O. Matveeva, A. E. Lebedev, M. U. Shkurnikov, V. V. Galatenko, U. Schumacher, A. G. Tonevitsky, J. Clin. Bioinform., 2013, 3,13.
A. A. Zakharyants, O. A. Burmistrova, M. Yu. Shkurnikov, A. A. Poloznikov, D. A. Sakharov, Klet. Tekhn. Biol. Med. [Cell. Technol. Biol. Med.], 2016, 3, 208 (in Russian).
A. A. Zakharyants, O. A. Burmistrova, A. A. Poloznikov, Byul. Eksperim. Biol. Med. [Bull. Exp. Biol. Med.], 2016, 162, 517 (in Russian).
J. H. Lewis, R. C. Ranard, A. Caruso, L. K. Jackson, F. Mullick, K. G. Ishak, L. B. Seeff, H. J. Zimmerman, Hepatology, 1989, 9,679.
M. E. Elsherbiny, A. O. S. El-Kadi, D. R. Brocks, J. Pharm. Pharm. Sci., 2008, 11,147.
A. Zahno, K. Brecht, R. Morand, S. Maseneni, M. Török, P. W. Lindinger, S. Krähenbühl, Biochem. Pharmacol., 2011, 81,432.
Q. Wu, B. Ning, J. Xuan, Z. Ren, L. Guo, M. S. Bryant, Toxicol. Lett., 2016, 253,55.
K. Ohyama, M. Nakajima, S. Nakamura, N. Shimada, H. Yamazaki, T. Yokoi, Drug Metab. Dispos., 2000, 28, 1303.
S. J. Baldwin, S. E. Clarke, R. J. Chenery, Br. J. Clin. Pharmacol., 1999, 48,424.
I. Bachmakov, H. Glaeser, M. F. Fromm, J. König, Diabetes, 2008, 57, 1463.
S. J. Hemauer, S. L. Patrikeeva, T. N. Nanovskaya, G. D. V. Hankins, M. S. Ahmed, Am. J. Obstet. Gynecol., 2010, 202, 383.e1.
J. Weiss, A. Sauer, M. Herzog, R. H. Böger, W. E. Haefeli, R. A. Benndorf, Pharmacology, 2009, 84,264.
J. W. Higgins, A. B. Ke, M. J. Zamek-Gliszczynski, Drug Metab. Dispos., 2014, 42, 1780.
C. Seral, J.-M. Michot, H. Chanteux, M.-P. Mingeot-Leclercq, P. M. Tulkens, F. van Bambeke, Antimicrob. Agents Chemother., 2003, 47, 1047.
K. S. Fenner, M. D. Troutman, S. Kempshall, J. A. Cook, J. A. Ware, D. A. Smith, C. A. Lee, Clin. Pharmacol. Ther., 2009, 85,173.
E. Wang, W. W. Johnson, Chemotherapy, 2003, 49,303.
T. Nakanishi, Cancer Genomics Proteomics, 2007, 4,241.
M. Takano, R. Hasegawa, T. Fukuda, R. Yumoto, J. Nagai, T. Murakami, Eur. J. Pharmacol., 1998, 358,289.
H. Yamazaki, T. Shimada, Drug Metab. Dispos., 1998, 26, 1053.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0150—0155, January, 2017.
Rights and permissions
About this article
Cite this article
Nikulin, S.V., Tonevitsky, E.A. & Poloznikov, A.A. Effect of ketoconazole on the transport and metabolism of drugs in the human liver cell model. Russ Chem Bull 66, 150–155 (2017). https://doi.org/10.1007/s11172-017-1713-z
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11172-017-1713-z