Division of Clinical Pharmacology and Toxicology, University Hospital Basel, 4031, Basel, Switzerland.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Clin Pharmacokinet. 2022 Jul;61(7):1039-1055. doi: 10.1007/s40262-022-01119-0. Epub 2022 May 16.
Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.
In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.
We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).
While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.
Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.
NCT03337945.
肝细胞色素 P450 酶（CYPs）的活性与药物在肝脏中的清除有关，已知在肝硬化患者中降低。几项研究报告了肝硬化对 CYP 活性的影响，但结果部分相互矛盾，且有些 CYP 缺乏。
本研究采用巴塞尔表型鸡尾酒法，旨在研究不同 Child 阶段（A-C）肝硬化患者的 CYP 活性。
我们评估了巴塞尔表型鸡尾酒（CYP1A2：咖啡因，CYP2B6：依非韦伦，CYP2C9：氟比洛芬，CYP2C19：奥美拉唑，CYP2D6：美托洛尔，CYP3A：咪达唑仑）的六种化合物及其 CYP 特异性代谢物的药代动力学，纳入了 16 名肝硬化 Child A 期患者（Child A 肝硬化组）、15 名肝硬化 Child B 期患者（Child B 肝硬化组）、5 名肝硬化 Child C 期患者（Child C 肝硬化组）和 12 名匹配的对照组。
虽然肝硬化仅轻度影响低至中度提取药物依非韦伦和氟比洛芬的药代动力学，但咖啡因的消除率在 Child C 肝硬化患者中降低了 51%。对于中等至高提取药物奥美拉唑、美托洛尔和咪达唑仑，肝硬化使清除率降低了 75%、37%和 60%，分别增加了暴露量，降低了表观全身清除率（清除率/生物利用度）。在 Child C 肝硬化患者中，代谢比（代谢物的 0 至 24 小时血浆浓度-时间曲线下面积与母体化合物的比值），一种 CYP 活性标志物，分别下降了 66%、47%、92%、73%和 43%，对于对黄嘌呤/咖啡因（CYP1A2）、8-羟基依非韦伦/依非韦伦（CYP2B6）、5-羟基奥美拉唑/奥美拉唑（CYP2C19）、α-羟美托洛尔/美托洛尔（CYP2D6）和 1'-羟基咪达唑仑/咪达唑仑（CYP3A）。相比之下，4-羟基氟比洛芬/氟比洛芬（CYP2C9）的代谢比保持不变。
肝硬化对 CYP 同工酶的活性有不同的影响。在肝硬化患者中，必须考虑药物剂量调整的这种变异性。
NCT03337945。
