Abstract：
This study aimed to investigate the possible drug-drug interactions (DDIs) of 5-FU with antihypertensives metabolised by CYP3A4 and 2C9, using blood pressure (BP) as a pharmacodynamic (PD) parameter. Patients who received 5-FU in combination with antihypertensives metabolised by CYP3A4 or 2C9, specifically, a) amlodipine, nifedipine, or amlodipine + nifedipine, b) candesartan or valsartan, or c) amlodipine + candesartan, amlodipine + losartan, or nifedipine + valsartan, (Group A, n = 20) were identified. Patients who received 5-FU with WF and antihypertensives, specifically, a) amlodipine or b) amlodipine + telmisartan, amlodipine + candesartan, or amlodipine + valsartan, (Group B, n = 5) or 5-FU alone (Group C, n = 25) were also identified and analysed as a comparator and control group, respectively. Regarding the peak BP levels during chemotherapy, there was a significant increase in both SBP (P < 0.0002 and 0.0013) and DBP (P = 0.0243 and 0.0032) in Groups A and C, respectively (Tukey-Kramer test). In contrast, although SBP also increased in Group B during chemotherapy, the change was not statistically significant and there was a decrease in DBP. The significant increase in SBP can be attributed to chemotherapy-induced hypertension by 5-FU or other drugs in the chemotherapeutic regimens. However, when comparing the lowest BP levels during chemotherapy, there was a decrease in SBP and DBP in all groups from the baseline values. The median time to peak and lowest BP was at least 2 weeks and 3 weeks, respectively, for all groups, suggesting that a BP lowering effect was observed following the offset of the initial chemotherapy-induced hypertension. At least 1 month after 5-FU chemotherapy, the SBP and DBP returned to baseline values in all groups. Since Group B also showed a significant increase in PT-INR, possibly demonstrating 5-FU inhibition of CYP activity and, consequently, of WF metabolism, it is likely that 5-FU also inhibited the metabolism of the antihypertensive drugs. The findings suggest possible DDIs between 5-FU and antihypertensives metabolised by CYP3A4.
摘要：
本研究旨在使用血压（BP）作为药效学（PD）参数，研究5-FU与CYP3A4和2C9代谢的抗高血压药的可能的药物-药物相互作用（DDI）。接受5-FU联合CYP3A4或2C9代谢的抗高血压药的患者，特别是，a)氨氯地平，硝苯地平,或氨氯地平+硝苯地平,b)坎地沙坦或缬沙坦，或c)氨氯地平+坎地沙坦，氨氯地平+氯沙坦,或者硝苯地平+缬沙坦,(A组,n=20)被鉴定。接受WF和抗高血压药5-FU的患者，具体来说,a)氨氯地平或b)氨氯地平+替米沙坦,氨氯地平+坎地沙坦，或氨氯地平+缬沙坦，(B组,n=5)或单独使用5-FU(C组，n=25)也被确定和分析为比较组和对照组，分别。关于化疗期间的峰值血压水平，A组和C组的SBP（P<0.0002和0.0013）和DBP（P=0.0243和0.0032）均显著增加，分别(Tukey-Kramer测试)。相比之下,尽管B组化疗期间SBP也增加，这一变化无统计学意义,DBP下降.SBP的显着增加可归因于化疗方案中5-FU或其他药物引起的化疗诱导的高血压。然而,当比较化疗期间的最低血压水平时，所有组的SBP和DBP均较基线值有所下降.达到峰值和最低BP的中位时间至少为2周和3周，分别,对于所有组，提示在初始化疗诱导的高血压抵消后观察到了降低BP的作用.5-FU化疗后至少1个月，所有组的SBP和DBP均恢复至基线值.由于B组PT-INR也有显著增加,可能证明5-FU抑制CYP活性，因此,WF的新陈代谢，5-FU也可能抑制抗高血压药物的代谢。研究结果表明，5-FU与CYP3A4代谢的抗高血压药之间可能存在DDI。
