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Rapid CommunicationShort Communication

Evaluation of 23 Lots of Commercially Available Cryopreserved Hepatocytes for Induction Assays of Human Cytochromes P450

Kanako Yajima, Yasuhiro Uno, Norie Murayama, Shotaro Uehara, Makiko Shimizu, Chika Nakamura, Kazuhide Iwasaki, Masahiro Utoh and Hiroshi Yamazaki
Drug Metabolism and Disposition May 2014, 42 (5) 867-871; DOI: https://doi.org/10.1124/dmd.113.056804
Kanako Yajima
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Yasuhiro Uno
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Norie Murayama
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Shotaro Uehara
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Makiko Shimizu
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Chika Nakamura
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Kazuhide Iwasaki
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Masahiro Utoh
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Hiroshi Yamazaki
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (K.Y., Y.U., S.U., C.N., K.I., M.U.); and Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan (N.M., M.S., H.Y.)
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Abstract

Due to the importance of in vitro cytochrome P450 (P450) induction assay to assess the possible drug-drug interaction events, the recent US Food and Drug Administration draft guidance and European Medicines Agency guideline recommend to assess P450 induction using fresh or cryopreserved hepatocytes at mRNA level and/or enzyme activity level. Although cryopreserved hepatocytes are commercially available for P450 induction assays, feasibility and practicability of these hepatocytes have not been fully investigated. In this study, a total of 23 lots of human cryopreserved hepatocytes were treated with three typical inducers (omeprazole, phenobarbital, and rifampicin), and induction of CYP1A2, CYP2B6, and CYP3A4 enzyme activity was measured. In 8 of these 23 hepatocyte lots, induction of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 mRNA was also analyzed. The results revealed that CYP1A2, CYP2B6, and CYP3A4 were induced (>2.0-fold) by omeprazole, phenobarbital, and rifampicin, respectively, in all the hepatocyte lots tested at enzyme activity level (23 lots) and mRNA level (8 lots). In contrast, of the 8 hepatocyte lots treated with rifampicin, CYP2C8 and CYP2C9 mRNA were not induced in 5 and 2 hepatocyte lots, respectively, and CYP2C19 mRNA was not induced in any of the 8 hepatocyte lots tested. These results suggest that induction of CYP1A2, CYP2B6, and CYP3A4 can be readily assessed, but evaluation for CYP2C mRNA induction might not be feasible, using commercially available human cryopreserved hepatocytes.

Footnotes

    • Received December 30, 2013.
    • Accepted February 19, 2014.
  • K.Y. and Y.U. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.113.056804.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (5)
Drug Metabolism and Disposition
Vol. 42, Issue 5
1 May 2014
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Rapid CommunicationShort Communication

P450 mRNA Induction in Cryopreserved Human Hepatocytes

Kanako Yajima, Yasuhiro Uno, Norie Murayama, Shotaro Uehara, Makiko Shimizu, Chika Nakamura, Kazuhide Iwasaki, Masahiro Utoh and Hiroshi Yamazaki
Drug Metabolism and Disposition May 1, 2014, 42 (5) 867-871; DOI: https://doi.org/10.1124/dmd.113.056804

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Rapid CommunicationShort Communication

P450 mRNA Induction in Cryopreserved Human Hepatocytes

Kanako Yajima, Yasuhiro Uno, Norie Murayama, Shotaro Uehara, Makiko Shimizu, Chika Nakamura, Kazuhide Iwasaki, Masahiro Utoh and Hiroshi Yamazaki
Drug Metabolism and Disposition May 1, 2014, 42 (5) 867-871; DOI: https://doi.org/10.1124/dmd.113.056804
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