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Research ArticleArticle

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

Linda Björkhem-Bergman, Tobias Bäckström, Hanna Nylén, Yuko Rönquist-Nii, Eva Bredberg, Tommy B. Andersson, Leif Bertilsson and Ulf Diczfalusy
Drug Metabolism and Disposition August 2013, 41 (8) 1488-1493; DOI: https://doi.org/10.1124/dmd.113.052316
Linda Björkhem-Bergman
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Tobias Bäckström
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Hanna Nylén
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Yuko Rönquist-Nii
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Eva Bredberg
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Tommy B. Andersson
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Leif Bertilsson
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Ulf Diczfalusy
Divisions of Clinical Pharmacology (L.B.-B., T.B., Y.R.-N., L.B.) and Clinical Chemistry (H.N., U.D.), Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; Astra Zeneca, R&D Mölndal, Mölndal (E.B., T.B.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.)
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Abstract

CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P < 0.01), and the 6β-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.

Footnotes

    • Received April 9, 2013.
    • Accepted May 14, 2013.
  • The study was financially supported by AstraZeneca, Sweden; and with grants from Swedish Research Council (No. 3902); the Swedish Foundation for Clinical Pharmacology and Pharmacotherapy; and through the regional agreement on training and clinical research (ALF) between Karolinska Institutet and Stockholm County Council.

  • L.B.-B. holds a postdoctoral financed by Karolinska Institutet and Stockholm County Council (KI/SLL). T.B.A. and E.B. are employees of AstraZeneca. Unrestricted financial support was provided by AstraZeneca. This has not influenced the design or the interpretation of the results of this study.

  • dx.doi.org/10.1124/dmd.113.052316.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

4β-Hydroxycholesterol and Midazolam as Markers of CYP3A4

Linda Björkhem-Bergman, Tobias Bäckström, Hanna Nylén, Yuko Rönquist-Nii, Eva Bredberg, Tommy B. Andersson, Leif Bertilsson and Ulf Diczfalusy
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1488-1493; DOI: https://doi.org/10.1124/dmd.113.052316

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Research ArticleArticle

4β-Hydroxycholesterol and Midazolam as Markers of CYP3A4

Linda Björkhem-Bergman, Tobias Bäckström, Hanna Nylén, Yuko Rönquist-Nii, Eva Bredberg, Tommy B. Andersson, Leif Bertilsson and Ulf Diczfalusy
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1488-1493; DOI: https://doi.org/10.1124/dmd.113.052316
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