Premium
CYP3A activity in severe liver cirrhosis correlates with C hild– P ugh and model for end‐stage liver disease ( MELD ) scores
Author(s) -
Albarmawi Albader,
Czock David,
Gauss Annika,
Ehehalt Robert,
Lorenzo Bermejo Justo,
Burhenne Jürgen,
Ganten Tom M.,
Sauer Peter,
Haefeli Walter E.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12182
Subject(s) - cirrhosis , midazolam , cyp3a , pharmacokinetics , liver disease , medicine , alcoholic liver disease , volume of distribution , liver function , gastroenterology , pharmacology , metabolism , cytochrome p450 , sedation
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 C hild– P ugh ( 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 ( CL u ), 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 : CL u = 843 ± 346 l h −1 , MELD ≥ 15: CL u = 805 ± 474 l h −1 , controls: CL u = 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.