CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores.
Br J Clin Pharmacol
; 77(1): 160-9, 2014 Jan.
Article
em En
| MEDLINE
| ID: mdl-23772874
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Índice de Gravidade de Doença
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Midazolam
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Citocromo P-450 CYP3A
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Biomarcadores Farmacológicos
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Cirrose Hepática
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha