Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Department of Clinical Research, University Hospital Basel, Switzerland.
Eur J Pharm Sci. 2024 Nov 1;202:106885. doi: 10.1016/j.ejps.2024.106885. Epub 2024 Aug 23.
Phenotyping serves to estimate enzyme activities in healthy persons and patients in vivo. Low doses of enzyme-specific substrates are administered, and activities estimated using metabolic ratios (MR, calculated as AUC/AUC). We administered the Basel phenotyping cocktail containing caffeine (CYP1A2 substrate), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A) to 36 patients with liver cirrhosis and 12 control subjects and determined free and total plasma concentrations over 24 h. Aims were to assess whether MRs reflect CYP activities in patients with liver cirrhosis and whether MRs calculated with free plasma concentrations (MR) provide better estimates than with total concentrations (MR). The correlation of MR with MR was excellent (R >0.910) for substrates with low (<30 %, caffeine and metoprolol) and intermediate protein binding (≥30 and <99 %, midazolam and omeprazole) but weak (R <0.30) for substrates with high protein binding (≥99 %, efavirenz and flurbiprofen). The correlations between MR and MR with CYP activities were good (R >0.820) for CYP1A2, CYP2C19 and CYP2D6. CYP3A4 activity was reflected better by midazolam elimination than by midazolam MR or MR. The correlation between MR and MR with CYP activity was not significant or weak for CYP2B6 and CYP2C9. In conclusion, MRs of substrates with an extensive protein binding (>99 %) show high inter-patient variabilities and do not accurately reflect CYP activity in patients with liver cirrhosis. Protein binding of the probe drugs has a high impact on the precision of CYP activity estimates and probe drugs with low or intermediate protein binding should be preferred.
表型分析用于估计健康个体和患者体内的酶活性。给予低剂量的酶特异性底物，并使用代谢比（MR，计算为 AUC/AUC）估计活性。我们给 36 例肝硬化患者和 12 例对照患者施用含有咖啡因（CYP1A2 底物）、依非韦伦（CYP2B6）、氟比洛芬（CYP2C9）、奥美拉唑（CYP2C19）、美托洛尔（CYP2D6）和咪达唑仑（CYP3A）的巴塞尔表型分析鸡尾酒，并在 24 小时内测定游离和总血浆浓度。目的是评估 MR 是否反映肝硬化患者的 CYP 活性，以及使用游离血浆浓度（MR）计算的 MR 是否比总浓度（MR）提供更好的估计。对于低蛋白结合率（<30%，咖啡因和美托洛尔）和中蛋白结合率（≥30%且<99%，咪达唑仑和奥美拉唑）的底物，MR 与 MR 的相关性非常好（R>0.910），但对于高蛋白结合率（≥99%，依非韦伦和氟比洛芬）的底物，相关性较弱（R<0.30）。MR 与 CYP 活性之间的相关性对于 CYP1A2、CYP2C19 和 CYP2D6 较好（R>0.820）。与咪达唑仑 MR 或 MR 相比，咪达唑仑清除更能反映 CYP3A4 活性。MR 与 CYP 活性之间的相关性对于 CYP2B6 和 CYP2C9 不显著或较弱。总之，蛋白结合率>99%的底物的 MR 具有较高的个体间变异性，不能准确反映肝硬化患者的 CYP 活性。探针药物的蛋白结合对 CYP 活性估计的精度有很大影响，应优先选择低或中蛋白结合的探针药物。
