title: CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Albader
authors.initials: A
authors.lastname: Albarmawi
authors.forename: David
authors.initials: D
authors.lastname: Czock
authors.forename: Annika
authors.initials: A
authors.lastname: Gauss
authors.forename: Robert
authors.initials: R
authors.lastname: Ehehalt
authors.forename: Justo
authors.initials: J
authors.lastname: Lorenzo Bermejo
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
authors.forename: Peter
authors.initials: P
authors.lastname: Sauer
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: Child-Pugh score; MELD score; cytochrome P450 CYP3A; liver cirrhosis; midazolam; pharmacokinetics