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Research ArticleArticle

Identification of a Functional Homolog of the Mammalian CYP3A4 in Locusts

Line Rørbæk Olsen, Charlotte Gabel-Jensen, Peter Aadal Nielsen, Steen Honoré Hansen and Lassina Badolo
Drug Metabolism and Disposition July 2014, 42 (7) 1153-1162; DOI: https://doi.org/10.1124/dmd.114.057430
Line Rørbæk Olsen
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (L.R.O., C.G.-J., S.H.H.); Department of Discovery ADME, H. Lundbeck A/S, Valby, Denmark (L.B.); and EntomoPharm R&D, Lund, Sweden (P.A.N.)
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Charlotte Gabel-Jensen
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (L.R.O., C.G.-J., S.H.H.); Department of Discovery ADME, H. Lundbeck A/S, Valby, Denmark (L.B.); and EntomoPharm R&D, Lund, Sweden (P.A.N.)
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Peter Aadal Nielsen
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (L.R.O., C.G.-J., S.H.H.); Department of Discovery ADME, H. Lundbeck A/S, Valby, Denmark (L.B.); and EntomoPharm R&D, Lund, Sweden (P.A.N.)
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Steen Honoré Hansen
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (L.R.O., C.G.-J., S.H.H.); Department of Discovery ADME, H. Lundbeck A/S, Valby, Denmark (L.B.); and EntomoPharm R&D, Lund, Sweden (P.A.N.)
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Lassina Badolo
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (L.R.O., C.G.-J., S.H.H.); Department of Discovery ADME, H. Lundbeck A/S, Valby, Denmark (L.B.); and EntomoPharm R&D, Lund, Sweden (P.A.N.)
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Abstract

Insects have been proposed as a new tool in early drug development. It was recently demonstrated that locusts have an efflux transporter localized in the blood-brain barrier (BBB) that is functionally similar to the mammalian P-glycoprotein efflux transporter. Two insect BBB models have been put forward, an ex vivo model and an in vivo model. To use the in vivo model it is necessary to fully characterize the locust as an entire organism with regards to metabolic pathways and excretion rate. In the present study, we have characterized the locust metabolism of terfenadine, a compound that in humans is specific to the cytochrome P450 enzyme 3A4. Using high-resolution mass spectrometry coupled to ultra-high-performance liquid chromatography, we have detected metabolites identical to human metabolites of terfenadine. The formation of human metabolites in locusts was inhibited by ketoconazole, a mammalian CYP3A4 inhibitor, suggesting that the enzyme responsible for the human metabolite formation in locusts is functionally similar to human CYP3A4. Besides the human metabolites of terfenadine, additional metabolites were formed in locusts. These were tentatively identified as phosphate and glucose conjugates. In conclusion, not only may locusts be a model useful for determining BBB permeation, but possibly insects could be used in metabolism investigation. However, extensive characterization of the insect model is necessary to determine its applicability.

Footnotes

    • Received January 31, 2014.
    • Accepted April 28, 2014.
  • This work was supported by the Danish National Advanced Technology Foundation [Grant 023-2011-3].

  • dx.doi.org/10.1124/dmd.114.057430.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (7)
Drug Metabolism and Disposition
Vol. 42, Issue 7
1 Jul 2014
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Research ArticleArticle

Comparison of Terfenadine Metabolism in Locusts and HLMs

Line Rørbæk Olsen, Charlotte Gabel-Jensen, Peter Aadal Nielsen, Steen Honoré Hansen and Lassina Badolo
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1153-1162; DOI: https://doi.org/10.1124/dmd.114.057430

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Research ArticleArticle

Comparison of Terfenadine Metabolism in Locusts and HLMs

Line Rørbæk Olsen, Charlotte Gabel-Jensen, Peter Aadal Nielsen, Steen Honoré Hansen and Lassina Badolo
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1153-1162; DOI: https://doi.org/10.1124/dmd.114.057430
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