Division of Clinical Pharmacology and Toxicology, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.
Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland.
Clin Pharmacol Ther. 2021 Jun;109(6):1668-1676. doi: 10.1002/cpt.2146. Epub 2021 Jan 8.
Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL-6, IL-1β, TNF-α, and IFN-γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL-6, and TNF-α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform-specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.
细胞色素 P450（CYP）的活性由于遗传和环境因素以及某些疾病而存在重要的个体间变异性。有限的人类数据支持炎症下调 CYP 活性的观点。我们的研究旨在评估骨科手术（急性炎症模型）对六种人类 CYP 活性的影响。这项前瞻性观察研究在瑞士日内瓦大学医院接受择期髋关节手术的 30 名患者中进行。含有咖啡因、安非他酮、氟比洛芬、奥美拉唑、右美沙芬和咪达唑仑作为探针药物的日内瓦表型鸡尾酒分别评估 CYP1A2、2B6、2C9、2C19、2D6 和 3A 活性，在手术前、术后第 1 天（D1）和第 3 天（D3）以及出院时口服给药。鸡尾酒摄入后 2 小时采集毛细血管血样以评估代谢比（MRs）。还测量血液中的血清炎症标志物（CRP、IL-6、IL-1β、TNF-α 和 IFN-γ）。CYP1A2 MRs 在基线和 D1 时的最低点下降了 53%（P<0.0001）。CYP2C19 和 CYP3A 活性（MRs）分别下降了 57%（P=0.0002）和 61%（P<0.0001），最低点出现在 D3。CYP2B6 和 CYP2C9 MRs 分别增加了 120%（P<0.0001）和 79%（P=0.018），并在 D1 时达到峰值。手术对 CYP2D6 MR 没有显著影响。髋关节手术是一种很好的急性炎症模型，因为 CRP、IL-6 和 TNF-α 的峰值水平在 D1 和第 2 天（D2）之间达到。急性炎症以同工酶特异性方式调节 CYP 活性，具有不同的幅度和动力学。因此，急性炎症可能对这些 CYP 底物的药代动力学具有临床相关影响。
