CYP3A activity in severe liver cirrhosis correlates with Child–Pugh and model for end-stage liver disease (MELD) scores

Authors

  • Albader Albarmawi,

    1. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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    • Authors contributed equally to the work.
  • David Czock,

    1. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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    • Authors contributed equally to the work.
  • Annika Gauss,

    1. Department of Internal Medicine IV, Gastroenterology, Infectious Diseases, and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
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  • Robert Ehehalt,

    1. Department of Internal Medicine IV, Gastroenterology, Infectious Diseases, and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
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  • Justo Lorenzo Bermejo,

    1. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
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  • Jürgen Burhenne,

    1. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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  • Tom M. Ganten,

    1. Department of Internal Medicine IV, Gastroenterology, Infectious Diseases, and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
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  • Peter Sauer,

    1. Department of Internal Medicine IV, Gastroenterology, Infectious Diseases, and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
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  • Walter E. Haefeli

    Corresponding author
    1. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
    • Correspondence

      Prof Walter E. Haefeli MD, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

      Tel.: +4962 2156 8740

      Fax: +4962 2156 4642

      E-mail: walter.emil.haefeli@med.uni-heidelberg.de

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Abstract

Aims

Impaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether Child–Pugh (CP) and model for end-stage liver disease (MELD) scores correlate with drug clearance.

Methods

Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis (n = 4, 10 and 10 with CP class A, B and C, respectively) and six patients without liver disease.

Results

Both scores correlated well with unbound midazolam clearance (CLu), unbound midazolam fraction and half-life (all P < 0.01), whereas the unbound steady-state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls (CP C: CLu = 843 ± 346 l h−1, MELD ≥ 15: CLu = 805 ± 474 l h−1, controls: CLu = 5815 ± 2649 l h−1, P < 0.01).

Conclusion

The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolizing enzyme subfamily in humans.

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