Albarmawi Albader, Czock David, Gauss Annika, Ehehalt Robert, Lorenzo Bermejo Justo, Burhenne Jürgen, Ganten Tom M, Sauer Peter, Haefeli Walter E
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Br J Clin Pharmacol. 2014 Jan;77(1):160-9. doi: 10.1111/bcp.12182.
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.
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.
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).
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.
肝功能受损常常需要调整药物剂量以避免药物过度蓄积和不良事件，但目前缺乏一个可用于衡量所需调整幅度的指标。本研究旨在探讨Child-Pugh（CP）评分和终末期肝病模型（MELD）评分是否与药物清除率相关。
使用咪达唑仑作为CYP3A探针，对24例轻度至重度肝硬化患者（分别为4例、10例和10例CP A级、B级和C级患者）以及6例无肝病患者的药代动力学进行分析。
两种评分均与游离咪达唑仑清除率（CLu）、游离咪达唑仑分数和半衰期显著相关（均P < 0.01），而游离稳态分布容积无显著变化。在重度肝硬化患者中，游离咪达唑仑清除率仅为对照组的14%（CP C级：CLu = 843 ± 346 l h-1，MELD≥15：CLu = 805 ± 474 l h-1，对照组：CLu = 5815 ± 2649 l h-1，P < 0.01）。
与游离咪达唑仑清除率的相关性表明，这两种评分均可预测CYP3A的代谢能力，CYP3A是人类最主要的药物代谢酶亚家族。
