Tarantino Giovanni, Capone Domenico, Contaldi Paola, Gianno Adriana, Teresa Mosca, Tufano Antonella
1 Department of Clinical Medicine and Surgery, "Federico II" University, Naples, Italy.
2 Integrated Care Department of Clinical Neurosciences, Anesthesiology and Drug-Use, Section of Clinical Pharmacology, "Federico II" University, Naples, Italy.
Clin Appl Thromb Hemost. 2018 Sep;24(6):928-935. doi: 10.1177/1076029617733040. Epub 2017 Oct 9.
Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = -0.15, standard error = 0.04, 95% confidence interval = -0.24 to -0.06, t = -3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.
华法林是一种口服抗凝剂，常用于静脉和动脉血栓栓塞事件的一级和二级预防。该药物的特点是治疗指数窄、临床反应个体差异大以及不良事件发生率高，尤其是出血并发症。由于这些原因，必须通过国际标准化比值频繁评估凝血状态来密切监测剂量。华法林由肝细胞色素P-450代谢。高CYP 450活性可能导致药物浓度低，需要高剂量华法林才能达到疗效；相反，低CYP 450活性会导致药物浓度高，需要低剂量以避免潜在的毒性风险。参与华法林钠代谢的CYP主要同工酶是CYP1A2（针对R-华法林）和CYP2C9（针对S-华法林）。检测CYP1A2的探针是非那西丁和咖啡因，而检测CYP2C9的探针是甲苯磺丁脲。虽然S-华法林具有主要活性，但出于伦理问题决定不进行其表型分析，因为必须使用一种药物（甲苯磺丁脲）。相反，选择检测1A2同工酶，因为可以通过使用含咖啡因饮料中的咖啡因来研究后者同工酶的活性。具体而言，在禁食含咖啡因饮料过夜后，采用单点唾液咖啡因浓度（总过夜唾液咖啡因评估 [TOSCA]）。在本研究中，纳入了75名定期接受华法林钠治疗的非吸烟患者。结果显示华法林剂量与TOSCA值之间存在显著关联（系数 = -0.15，标准误差 = 0.04，95%置信区间 = -0.24至 -0.06，t = -3.23，P = .002）。总之，如果进一步得到证实，通过TOSCA对CYP1A2进行表型分析可能有助于管理服用华法林的患者，以减少严重不良事件。
