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Research ArticleArticle

Effect of Solvents on the Time-Dependent Inhibition of CYP3A4 and the Biotransformation of AZD3839 in Human Liver Microsomes and Hepatocytes

Jenny Aasa, Yin Hu, Göran Eklund, Anders Lindgren, Pawel Baranczewski, Jonas Malmquist, Dominika Turek and Tjerk Bueters
Drug Metabolism and Disposition January 2013, 41 (1) 159-169; DOI: https://doi.org/10.1124/dmd.112.047597
Jenny Aasa
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Yin Hu
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Göran Eklund
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Anders Lindgren
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Pawel Baranczewski
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Jonas Malmquist
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Dominika Turek
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Tjerk Bueters
Drug Metabolism & Pharmacokinetics, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (J.A., Y.H., G.E., A.L., P.B., T.B.); Medicinal Chemistry, Central Nervous System & Pain iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden (D.T.); Global Drug Metabolism & Pharmacokinetics Screening and Profiling, AstraZeneca R&D, Södertälje, Sweden (J.M.); and MetaSafe AB, Södertälje, Sweden (G.E.)
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Abstract

Time-dependent inhibition (TDI) of the cytochrome P450 (P450) family of enzymes is usually studied in human liver microsomes (HLM) by investigating whether the inhibitory potency is increased with increased incubation times. The presented work was initiated after a discrepancy was observed for the TDI of an important P450 enzyme, CYP3A4, during early studies of the investigational drug compound AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate]; TDI was detected using a regulatory method but not with an early screening method. We show here that the different solvents present in the respective studies, dimethyl sulfoxide (DMSO, screening method) versus methanol or water (regulatory method), were responsible for the different TDI results. We further demonstrate why DMSO, present at the levels of 0.2% and 0.5% in the incubations, masked the TDI effect. In addition to the TDI experiments performed in HLM, TDI studies with AZD3839 were performed in pooled human hepatocytes (Hhep) from different suppliers, using DMSO, methanol, or water. The results from these experiments show no TDI or attenuated TDI effect, depending on the supplier. Metabolite identification of the compound dissolved in DMSO, methanol, or water shows different profiles after incubations with the different systems (HLM or Hhep), which may explain the differences in the TDI outcomes. Thorough investigations of the biotransformation of AZD3839 have been performed to find the reactive pathway causing the TDI of CYP3A4, and are presented here. Our findings show that the in vitro risk profile for drug-drug interactions potential of AZD3839 is very much dependent on the chosen test system and the experimental conditions used.

Footnotes

  • dx.doi.org/10.1124/dmd.112.047597.

  • Received July 2, 2012.
  • Accepted October 16, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleArticle

Effect of Solvents on the TDI of CYP3A4

Jenny Aasa, Yin Hu, Göran Eklund, Anders Lindgren, Pawel Baranczewski, Jonas Malmquist, Dominika Turek and Tjerk Bueters
Drug Metabolism and Disposition January 1, 2013, 41 (1) 159-169; DOI: https://doi.org/10.1124/dmd.112.047597

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Research ArticleArticle

Effect of Solvents on the TDI of CYP3A4

Jenny Aasa, Yin Hu, Göran Eklund, Anders Lindgren, Pawel Baranczewski, Jonas Malmquist, Dominika Turek and Tjerk Bueters
Drug Metabolism and Disposition January 1, 2013, 41 (1) 159-169; DOI: https://doi.org/10.1124/dmd.112.047597
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