质子泵抑制剂药动学相互作用研究进展

目的 探讨质子泵抑制剂药动学相互作用的研究进展。方法 对国内外相关领域的文献进行归纳和总结。结果 系统地对质子泵抑制剂通过提高胃内pH值和抑制P-糖蛋白影响相关药物吸收，抑制CYP2C19和CYP3A4影响相关药物代谢，抑制相关药物经肾清除等进行阐述。重点介绍了质子泵抑制剂与地高辛、伊曲康唑、酪氨酸激酶抑制剂、氯吡格雷、华法林、甲氨蝶呤、顺铂和培美曲塞的相互作用。结论 临床用药应密切关注药物相互作用，避免质子泵抑制剂与此类药物联合使用或选用相互作用较小的质子泵抑制剂。     

重症患者伏立康唑血药谷浓度监测分析

目的 通过分析重症患者伏立康唑血药谷浓度的变化,探讨重症患者最优化的伏立康唑给药方案。方法 采用回顾性分析研究,选择2014年12月-2016年12月入住南京大学医学院附属鼓楼医院重症医学科使用伏立康唑并监测伏立康唑血药谷浓度的重症患者,从性别、年龄、体重、APACHE2评分、剂量、总胆红素、白蛋白与浓度相关性,浓度分布情况、质子泵抑制剂对伏立康唑血药谷浓度的影响及疗效等进行统计分析。结果 共纳入99例患者,监测150例次伏立康唑血药谷浓度,其中仅76.00%（114/150）达目标范围1~5.5 mg/L,<1 mg/L占13.33%（17/150）,>5.5 mg/L占12.67%（19/150）;高龄患者（年龄 ≥ 60岁）伏立康唑血药谷浓度与中青年组相比有统计学差异（P<0.05）,多重线性回归分析显示,除年龄外（P=0.000）,性别、体重、体重标准化剂量、APACHE2评分、总胆红素及白蛋白对血药谷浓度的影响均无统计学意义;是否使用质子泵抑制剂与伏立康唑血药谷浓度无显著性差异（P=0.165）,联用泮托拉唑患者血药浓度呈上升趋势（P=0.054）,联用泮托拉唑与艾司奥美拉唑相比伏立康唑谷浓度比较有统计学差异（P=0.036）;伏立康唑达标者与未达标者病死率比较差异无统计学意义（χ²=0.059,P=0.809）。结论 伏立康唑血药谷浓度个体差异大,因此临床有监测的必要,年龄、联用质子泵抑制剂对伏立康唑血药谷浓度影响较大,制定给药方案时需考虑这些因素的影响。     

药物相互作用致华法林药效增强的病例分析

目的分析华法林治疗的药物相互作用,促进临床合理应用。方法对4例华法林治疗过程中发生出血病例的治疗方案进行讨论,分析参与华法林药物相互作用的药物,并分析可能的作用机制。结果胺碘酮、喹诺酮类和质子泵抑制剂等药物的联用可能是引起华法林代谢抑制,导致其抗凝作用增强并引起出血的主要原因。结论临床药师参与临床药物治疗有助于医师对药物相互作用引起的药物不良反应的识别,提高用药安全性。     

1例胺碘酮致华法林抗凝作用增强病例分析

目的 探讨临床药师在华法林抗凝治疗时联用胺碘酮引起国际标准化值(INR)异常升高的处理方法及药学监护。 方法 通过对照华法林与其他药物相互作用的情况,确定引起INR值异常波动的药物,及时调整华法林剂量,加强凝血功能的监测,并从华法林与胺碘酮的作用机制、相互作用、两药联用后抗凝作用与两药的剂量、浓度相关性等方面阐述胺碘酮对华法林抗凝作用的影响。 结果 INR异常波动为华法林与胺碘酮联用所致,两药联用可增强华法林的抗凝作用,增加出血风险,通过停用华法林3 d,INR恢复到目标值范围,继续给予华法林抗凝治疗,患者情况控制平稳,顺利出院。 结论 临床药师通过对患者有效的药学监护,可协助临床及时发现药物治疗相关问题。在使用与华法林有相互作用的药物时要考虑其对抗凝治疗的影响,一方面要充分了解药物合用时的药理学及药动学变化,另一方面要加强监测,以便及时调整用药方案,提高临床用药的安全性和合理性,更好地为患者提供药学服务。     

细胞色素P450酶2C9和维生素K环氧化物还原酶复合体1基因多态性对瓣膜置换术后华法林剂量影响分析

目的 分析细胞色素P450酶2C9（CYP2C9）和维生素K环氧化物还原酶复合体1（VKORC1）基因多态性对瓣膜置换术后华法林剂量的影响。方法 选取自2015年3月—2017年12月期间于漯河市中心医院行瓣膜置换术后口服华法林的127例患者为研究对象。采用PCR-RFLP法分别检测其CYP2C9和VKORC1基因型,同时记录患者的华法林日均服用剂量、血浆总浓度及游离浓度。对不同基因型及临床特征与华法林日常服用剂量进行直线相关及多元回归分析。结果 华法林日均服用剂量对比,CYP2C9（1061A/C）基因型AA患者显著高于基因型AC患者（P<0.05）,VKORC1（1639 G/A）基因型AA患者显著低于基因型AG患者（P<0.05）,VKORC1（1173 C/T）基因型TT患者显著低于基因型CT患者（P<0.05）。华法林血浆总浓度及游离浓度对比, VKORC1 （1639 G/A）基因型AA患者显著低于基因型AG患者（P<0.05）,VKORC1（1173 C/T）基因型TT患者显著低于基因型CT患者（P<0.05）。女性患者的华法林日均服用剂量显著低于男性患者（P<0.05）,≥70岁和60～69岁患者显著低于60岁以下各年龄段（P<0.05）。直线相关分析及多元回归分析结果提示,华法日均服用剂量与CYP2C9、VKORC1基因型和年龄、性别相关（P<0.05）。结论 CYP2C9和VKORC1基因多态性与瓣膜置换术后华法林日常服用剂量个体化相关,同时年龄和性别也是影响因素之一。     

心脏瓣膜置换术后患者使用质子泵抑制剂对华法林抗凝初期有效性及安全性的影响

目的：研究心脏瓣膜置换术后患者质子泵抑制剂（PPIs）对华法林抗凝初期的有效性及安全性的影响。方法：收集2013年1月至2014年12月在南京鼓楼医院行心脏瓣膜置换术后使用华法林联合PPIs的患者294例,根据术后使用PPIs的种类分为奥美拉唑组和泮托拉唑对照组。回顾性分析两组间PT值、INR值及华法林日剂量的差异,根据不良反应发生率及停药率评估PPIs与华法林联用的安全性。结果：两组间的华法林平均日剂量、INR值首次达标时间和住院期间INR的控制情况差异无统计学意义（P>0.05）。服药第1天和7天的INR值、PT值在两组间均无显著性差异（P>0.05）,第4天奥美拉唑组INR 1.84±0.49、PT（21.3±5.7）s,显著高于泮托拉唑组INR 1.71±0.37、PT（19.7±4.4）s,P<0.05。在INR 1.6~2.2亚组中,两组术后第4天的INR值分布存在显著性差异（P<0.05）。在安全性指标方面,奥美拉唑组的华法林停药率为（46.1%）,显著高于泮托拉唑组（25.25%）,INR>3的次数、栓塞率和出血率在两组间的差异均无统计学意义（P>0.05）。结论：心脏瓣膜置换术后的患者,在服用华法林抗凝的初期,奥美拉唑增强了华法林的抗凝效果,且影响华法林使用的安全性（如增加华法林的停药率）,两药联用时应当严密监测INR值,保证抗凝治疗的安全。     

抗凝药物华法林与牛血清白蛋白相互作用光谱研究

采用紫外-可见吸收光谱和荧光光谱，在生理pH条件下，研究华法林与牛血清白蛋白的相互作用。探讨华法林对于牛血清白蛋白的荧光猝灭机制。结果表明华法林对牛血清白蛋白的猝灭作用为动态猝灭过程。猝灭常数在16 ℃和37 ℃分别为6.05×10⁴ L·mol^-1和6.14×10⁴ L·mol^-1。根据Fster的偶极-偶极无辐射能量转移理论，求得牛血清白蛋白-华法林的能量转移效率E为0.37，两者间的最近距离r为3.15 nm。     

抗癫痫药物与华法林相互作用的研究进展

口服抗凝药华法林的抗凝作用受很多因素的影响,如患者的年龄、体重、合并症等。与其他药物的相互作用也是影响华法林抗凝作用的重要因素之一,其中一些抗癫痫药物对华法林的影响较大且机制复杂,作用持续时间也较长,对于联用华法林的癫痫患者,抗癫痫药物的选择与监测更为重要。本文通过整合国内外相关研究,探讨和总结华法林与抗癫痫药物间的相互作用机制和应对策略,比较不同抗癫痫药物的药代动力学特性及与华法林相互作用的差异,从而为抗癫痫药物的选择和相应剂量的调整提供参考,以降低用药风险。     

精神科住院患者医嘱中CYP450介导的药物相互作用风险分析

目的 调查河北医科大学第一医院精神科住院患者存在细胞色素P450酶（CYP450）介导的药物相互作用的住院医嘱，分析潜在具有临床意义的药物相互作用，为临床用药提供参考。方法 对河北医科大学第一医院2018年7月1日-12月31日精神科住院患者所有运行病历的用药情况进行统计分析，筛选联用≥ 2种药物的医嘱，记录联合用药中含有CYP450酶底物、抑制剂或诱导剂的情况。以代谢酶学理论为指导，以药品说明书、相关文献报道为基础，评价医嘱中潜在的代谢性药物相互作用，并统计临床发生实际药物相互作用的病例。结果 共查阅1 658份病历，其中存在代谢性药物相互作用的病历227份，占13.7%，涉及的CYP酶的亚型主要有CYP2D6（n=176，77.5%）、CYP3A4（n=105，46.3%）、CYP2C19（n=24，10.6%）和CYP2C9（n=5，2.2%）。临床发生实际药物相互作用的病历6份，占2.6%。结论 河北医科大学第一医院精神科住院患者病历中存在潜在的代谢性药物相互作用较多。为提高用药的疗效与安全，临床上应尽量避免联用已有文献报道的存在不良相互作用的药物，选择没有相互作用或相互作用较少的同类药物。     

肇庆地区人群华法林相关基因CYP2C9*3和VKORC1的多态性分布研究及指导价值

目的 探讨广东省肇庆地区人群华法林相关基因细胞色素P450复合物亚基2C9（CYP2C9）和维生素K环氧还原酶复合物亚基1（VKORC1）多态性分布,并比较性别和中国西双版纳傣族、北京汉族、南方汉族间差异性的分布,为临床医生精准使用华法林进行抗凝治疗提供理论基础。方法 选取2019年5月-2022年1月于肇庆市第一人民医院进行华法林相关基因检测的患者122例,所有患者均采用数字荧光分子杂交技术对CY92C9^*3和VKORC1进行基因多态性检测,比较患者性别间和中国西双版纳傣族、北京地区汉族、南方地区汉族间的基因多态性分布情况,并对比基于药物基因组学指导下的华法林使用剂量与常规剂量使用华法林治疗后2~3 d后国际标准化比值（INR）达标率。结果 122例检测样本中,CY92C9^*3基因位点AA、AC、CC基因型所占的比例分别为95.90%、4.10%、0,C等位基因和T等位基因频率分别为97.95%和2.05%;VKORC1基因位点GG、GA、AA基因型分别为0.82%、19.67%、79.51%,A等位基因和C等位基因频率分别为10.66%和89.34%。不同性别间CY92C9^*3与VKORC1的基因型分布和等位基因分布差异均无统计学意义（P>0.05）。通过已有的数据库进行对比,肇庆地区的CY92C9^*3基因型、等位基因与1000 Genomes Project （1000 GP）西双版纳傣族、北京汉族与南方汉族对比无统计学差异（P>0.05）;但与1000 GP北京汉族对比,VKORC1的基因型和等位基因频率有统计学差异（P<0.05）;与1000GP西双版纳傣族对比,VKORC1的等位基因频率有统计学差异（P<0.05）;华法林在基因组学指导下的剂量与常规剂量治疗后INR达标率差异有统计学意义（P<0.01）。结论 肇庆地区人群存在CY92C9^*3和VKORC1基因多态性,其中VKORC1基因可能存在地域的差异,进行华法林相关基因检测可以为临床制定个体化华法林抗凝方案提供重要的参考价值。     

Review article: proton pump inhibitors with clopidogrel--evidence for and against a clinically-important interaction

Aliment Pharmacol Ther 2011; 33: 758–767

Summary

Background The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited. Aim To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking. Methods A search of the published literature combined with the authors’ knowledge of the field. Results There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11 000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18 000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking. Conclusions Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven.     

Hepatic cytochrome P450 mediates interaction between warfarin and Coleus forskohlii extract in vivo and in vitro

Objectives This study aimed to determine whether Coleus forskohlii extract (CFE) influences the anticoagulant action of warfarin in mice in vivo and its relationship with hepatic cytochrome P450 (CYP). Methods Mice were fed various doses of CFE standardised with 10% forskolin in a normal diet for one week, or in protein diets containing 7% and 20% casein (low and normal) for four weeks. They were then administered with warfarin by gavage on the last two days of the treatment regimen, and blood coagulation parameters, as well as hepatic CYP, were analysed at 18 h after the last dose. Direct interaction between CFE and forskolin with CYP2C was evaluated in vitro. Key findings CFE dose dependently increased hepatic total CYP content and S‐warfarin 7‐hydroxylase activity at a dietary level of ≥0.05%. Warfarin‐induced anticoagulation was attenuated by CFE in parallel with CYP induction. The findings were similar in mice fed diets containing CFE and different ratios of protein. CFE directly inhibited CYP2C activity in mouse and human liver microsomes in vitro, whereas forskolin was only slightly inhibitory. Conclusions CFE attenuates the anticoagulant action of warfarin by inducing hepatic CYP2C; thus, caution is required with the combination of warfarin and dietary supplements containing CFE.     

胺碘酮和CYP2C9、VKORC1基因型对华法林抗凝效果的影响分析

分析胺碘酮在不同的CYP2C9和VKORC1分型患者对华法林的抗凝作用的影响。纳入从2008年9月至2009年11月某三甲医院应用华法林的入院患者,收集患者一般信息、合并用药及其他临床相关数据,检测患者VKORCl和CYP2C9基因型;比较使用或未使用胺碘酮治疗患者抗凝稳定期INR值及华法林用量,纳入基因分型进行华法林/胺碘酮相互作用的亚组分析。结果未发现胺碘酮应用患者华法林稳定期用量和INR值的统计学差异,基因型亚组差异无统计学意义。这说明院内短期合并使用胺碘酮患者对华法林稳定剂量和INR值无显著影响。     

Increased liability of tramadol–warfarin interaction in individuals with mutations in the cytochrome<Emphasis Type="Italic"> P</Emphasis><Subscript>450</Subscript> 2D6 gene

Objective This study aimed to investigate the importance of cytochrome P₄₅₀ enzymes for the reported interaction between tramadol and warfarin.Materials and methods Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.Results Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.Conclusion The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.     

质子泵抑制剂与氯吡格雷的药物相互作用解析

近年来,临床研究发现氯吡格雷合用质子泵抑制剂（proton pump inhibitors,PPI）可能会增加急性冠脉综合征（acute coronary syndrome,ACS）或经皮冠状动脉介入（percutaneous coronary intervention,PCI）术后患者心血管不良事件发生的风险,因此,联合用药存在争议。本文从氯吡格雷与CYP2C19多态性、PPI与氯吡格雷在药理及临床作用上的相互影响、相关临床研究来深入解析药物相互作用。药代动力学研究的Meta分析结果显示,PPI可能削弱了氯吡格雷抗血小板的效应。10个临床观察性研究都体现了这个观点,但文献质量偏低,而其余3篇低质量的观察性研究、5篇中等质量的观察性研究和1篇高质量的RCT均未发现氯吡格雷合用PPI会显著增加患者心血管不良事件的发生风险。     

Interaction potential between cranberry juice and warfarin.

PURPOSE: The interaction potential between warfarin and cranberry juice is discussed. SUMMARY: Reports from the United Kingdom have raised concern over the interaction potential between cranberry juice and warfarin. Warfarin is the most commonly prescribed oral medication for anticoagulation therapy. Cranberry juice is a flavonoid, which has been shown to induce, inhibit, or act as a substrate for the biosynthesis of several cytochrome P-450 (CYP) isoenzymes. Specifically, cranberry juice may inhibit the activity of CYP2C9, the primary isoenzyme involved in the metabolism of S-warfarin. A search of the medical literature identified three peer-reviewed case reports and two peer-reviewed, prospective, randomized, placebo-controlled clinical trials using metabolic surrogates of warfarin (flurbiprofen and cyclosporine) that described possible interactions between cranberry juice and warfarin. Two case reports suggested that cranberry juice increased the International Normalized Ratio (INR) of patients taking warfarin, but neither clearly identified cranberry juice as the sole cause of INR elevation. One case report appeared to show a correlation between the effects of cranberry juice and warfarin metabolism. Both clinical trials indicated the lack of an interaction between cranberry juice and CYP isoenzymes 2C9 and 3A, both of which are necessary in warfarin metabolism. More studies are required to determine the potential interaction between cranberry juice and warfarin. CONCLUSION: The available data do not seem to show a clinically relevant interaction between cranberry juice and warfarin; however, patients taking warfarin with cranberry juice should be cautioned about the potential interaction and monitored closely for INR changes and signs and symptoms of bleeding.     

Role of pharmacodiagnostic of CYP2C9 variants in the optimization of warfarin therapy in Malaysia: A 6-month follow-up study

1.?A retrospective study was conducted to explore the importance of CYP2C9 genotyping for the initiation and maintenance therapy of warfarin in clinical practice. A total of 191 patients on warfarin therapy in a local hospital were recruited after written informed consent. Their medical records were reviewed and no intervention of warfarin dose was performed.

2.?A total of 5 ml of blood were taken from each subject for DNA extraction and identification of *1, *2, *3 and *4 CYP2C9 alleles, using a nested-allele-specific-multiplex-polymerase chain reaction (PCR). Half the patients were Malays and the remaining were Chinese.

3.?Two genotypes were detected; 93.2% had CYP2C9*1/*1 and 6.8% were CYP2C9*1/* 3. Warfarin doses were higher in patients with CYP2C9*1/*1. Patients with the *1/* 3 genotype experienced a higher rate of serious and life-threatening bleeding; 15.4 versus 6.2 per 100 patients per 6 months.

4.?The observation clearly highlights the inadequacy of the current dosing regimens and the need to move toward a more individualized approach to warfarin therapy. Prospective clinical studies are now being conducted to assess dosing algorithms that incorporate the contribution of the genotype to allow the individualization of warfarin dose.