葡萄柚汁对药物的影响

葡萄柚汁低、用量小、代谢过程易受细胞色素P4503A4(CYP3A4)的影响，如非洛与许多药物能够发生不同程度的相互作用，大多数受影响的药物为口服生物利用度地平、洛伐他汀、特非那丁、西沙比利、咪达唑仑、沙奎那韦等。研究表明，葡萄柚汁能够抑制肠壁CYP3A4介导的药物氧化代谢过程，从而使得药效增强或不良反应增加，葡萄柚汁与药物相互作用存在个体差异，这与人体小肠CYP3A4活性有关。因此，在临床上应尽量避免这些药物与葡萄柚汁合用，确保用药安全。     

葡萄柚汁与钙通道阻滞药的相互作用

葡萄柚汁是果汁饮品的主要成分之一,钙通道阻滞药(CCB)是广泛用于高血压等心、脑血管疾病治疗的药物,研究证实两者合用时可能影响CCB的吸收与代谢,改变其药动学参数,并导致不良反应,其中尼卡地平、非洛地平、尼群地平等生物利用度较低,尤应引起关注。葡萄柚汁和CCB相互作用机制可能与葡萄柚汁抑制细胞色素P450 3A4(CYP3A4)活性、提高P-糖蛋白(P-gp)底物转运,而CCB则是CYP3A4和P-gp的底物有关。本文对近年来葡萄柚汁与CCB的食品-药物相互作用的研究进展做一综述。     

葡萄柚汁中的2个主要成分抑制肠内CYP3A4有不同的起始时间

葡萄柚汁可升高某些口服药物的血浓度,这主要是由于其抑制了肠中CYP3A4介导的首过代谢,它所含的2个主要化合物6＇,7＇-二羟基香柠檬亭（DHB）和香柠檬亭（BG）是引起葡萄柚汁与药物相互作用的重要成分。作者采用CYP3A4表达的Caco-2细胞和以不同的CYP3A4底物亚组（咪达唑仑和睾酮）为探针,     

石榴汁与葡萄柚汁对咪达唑仑口服或静脉给药清除率影响的比较研究

许多研究证明,葡萄柚汁等天然物质抑制肠内CYP3A同工酶,进而引起某些药物间相互作用。研究了石榴汁(PJ)体外对人肝微粒体和在人体实验中对健康志愿者体内细胞色素P450-3A(CYP3A)活性的影响,并与葡萄柚汁(GFJ)做了比较。体外研究采用无肝疾病的人肝脏微粒体。将咪达唑仑(250mmol     

LC-MS/MS法研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的体外抑制作用

目的：建立液相色谱-串联质谱法（LC-MS/MS）研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的 体外抑制作用。方法：采用ESI正离子和负离子选择反应检测同时测定扑热息痛、4-羟基甲苯磺丁脲、5-羟基奥美拉唑 、氧去甲基右美沙芬、6-羟基氯唑沙宗和氧化硝苯地平，分别代表CYP1A2，CYP2C9，CYP2C19，CYP2D6，CYP2E1， CYP3A4的活性；黄酮类化合物和6种探针底物在人肝微粒体中共同孵育，并计算其IC50值表示对CYP450酶的抑制程度。 结果：黄酮苷类（水飞蓟宾、金丝桃苷、儿茶素、表儿茶素、葛根素、芦丁、甘草苷以及柚皮苷）的IC50 值均大于50 μmol?L-1，对6种亚型没有抑制作用。而黄酮苷元如槲皮素等均能不同程度地抑制CYP1A2，IC50值从0.054 μmol?L-1 到31.91 μmol?L-1不等；有些对其他亚型如 CYP2C9，CYP2C19，CYP2E1，CYP3A4 也有一定的抑制作用。所有的黄酮类 化合物对CYP2D6无抑制活性。黄酮对CYP3A4的活性也有激活作用。结论：建立的LC-MS/MS方法准确、灵敏、可靠。33种 黄酮类化合物对CYP450酶6种亚型有不同的抑制作用，这些信息有助于中药-药物相互作用的预测。     

LC-MS/MS法研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的体外抑制作用

目的：建立液相色谱-串联质谱法（LC-MS/MS）研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的 体外抑制作用。方法：采用ESI正离子和负离子选择反应检测同时测定扑热息痛、4-羟基甲苯磺丁脲、5-羟基奥美拉唑 、氧去甲基右美沙芬、6-羟基氯唑沙宗和氧化硝苯地平，分别代表CYP1A2，CYP2C9，CYP2C19，CYP2D6，CYP2E1， CYP3A4的活性；黄酮类化合物和6种探针底物在人肝微粒体中共同孵育，并计算其IC50值表示对CYP450酶的抑制程度。 结果：黄酮苷类（水飞蓟宾、金丝桃苷、儿茶素、表儿茶素、葛根素、芦丁、甘草苷以及柚皮苷）的IC50 值均大于50 μmol?L-1，对6种亚型没有抑制作用。而黄酮苷元如槲皮素等均能不同程度地抑制CYP1A2，IC50值从0.054 μmol?L-1 到31.91 μmol?L-1不等；有些对其他亚型如 CYP2C9，CYP2C19，CYP2E1，CYP3A4 也有一定的抑制作用。所有的黄酮类 化合物对CYP2D6无抑制活性。黄酮对CYP3A4的活性也有激活作用。结论：建立的LC-MS/MS方法准确、灵敏、可靠。33种 黄酮类化合物对CYP450酶6种亚型有不同的抑制作用，这些信息有助于中药-药物相互作用的预测。     

LC-MS/MS法研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的体外抑制作用

目的：建立液相色谱-串联质谱法（LC-MS/MS）研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的 体外抑制作用。方法：采用ESI正离子和负离子选择反应检测同时测定扑热息痛、4-羟基甲苯磺丁脲、5-羟基奥美拉唑 、氧去甲基右美沙芬、6-羟基氯唑沙宗和氧化硝苯地平，分别代表CYP1A2，CYP2C9，CYP2C19，CYP2D6，CYP2E1， CYP3A4的活性；黄酮类化合物和6种探针底物在人肝微粒体中共同孵育，并计算其IC50值表示对CYP450酶的抑制程度。 结果：黄酮苷类（水飞蓟宾、金丝桃苷、儿茶素、表儿茶素、葛根素、芦丁、甘草苷以及柚皮苷）的IC50 值均大于50 μmol?L-1，对6种亚型没有抑制作用。而黄酮苷元如槲皮素等均能不同程度地抑制CYP1A2，IC50值从0.054 μmol?L-1 到31.91 μmol?L-1不等；有些对其他亚型如 CYP2C9，CYP2C19，CYP2E1，CYP3A4 也有一定的抑制作用。所有的黄酮类 化合物对CYP2D6无抑制活性。黄酮对CYP3A4的活性也有激活作用。结论：建立的LC-MS/MS方法准确、灵敏、可靠。33种 黄酮类化合物对CYP450酶6种亚型有不同的抑制作用，这些信息有助于中药-药物相互作用的预测。     

LC-MS/MS法研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的体外抑制作用

目的：建立液相色谱-串联质谱法（LC-MS/MS）研究黄酮类化合物对人肝微粒体细胞色素P450酶6种亚型的 体外抑制作用。方法：采用ESI正离子和负离子选择反应检测同时测定扑热息痛、4-羟基甲苯磺丁脲、5-羟基奥美拉唑 、氧去甲基右美沙芬、6-羟基氯唑沙宗和氧化硝苯地平,分别代表CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1, CYP3A4的活性;黄酮类化合物和6种探针底物在人肝微粒体中共同孵育,并计算其IC50值表示对CYP450酶的抑制程度。 结果：黄酮苷类（水飞蓟宾、金丝桃苷、儿茶素、表儿茶素、葛根素、芦丁、甘草苷以及柚皮苷）的IC50 值均大于50 μmol?L-1,对6种亚型没有抑制作用。而黄酮苷元如槲皮素等均能不同程度地抑制CYP1A2,IC50值从0.054 μmol?L-1 到31.91 μmol?L-1不等;有些对其他亚型如 CYP2C9,CYP2C19,CYP2E1,CYP3A4 也有一定的抑制作用。所有的黄酮类 化合物对CYP2D6无抑制活性。黄酮对CYP3A4的活性也有激活作用。结论：建立的LC-MS/MS方法准确、灵敏、可靠。33种 黄酮类化合物对CYP450酶6种亚型有不同的抑制作用,这些信息有助于中药-药物相互作用的预测。     

中药止咳橘红颗粒对CYP3A4和CYP1A2抑制作用的研究

目的：在人体内研究止咳橘红对CYP3A4和CYP1A2的抑制作用，以预测止咳橘红与常用临床药物的相互作用。方法：咪哒唑仑和咖啡因分别作为CYP3A4和A2的探针药物，采取交叉设计，10名受试者在服用3d止咳橘红的前后均服用7.5mg咪哒唑仑和100mg咖啡因，服药后采血测定两者及代谢产物的代谢动力学参数，探讨针药物及代谢物的浓度用HPLC-MS法测定，Cmax,tmax从药时曲线中直接读出，AUC用梯形法计算，Ke用3P87程序进行拟合计算，分析服药前后CYP3A4和CYP1A2被抑制的情况，结果 服用止咳橘红后，咪哒唑仑的代谢受到了轻微的抑制，它的血药浓度，达峰时间和药时曲线下面积都有了升高趋势，但无显著差异。而咖啡因的代谢未受到影响。结论 止咳橘红对CYP3A4的活性有较弱的抑制作用，能够导致CYP3A4底物咪哒唑仑代谢的轻微抑制，而对CYP1A2的活性没有影响。止咳橘红长期使用或超过治疗剂量使用时是否会对CYP3A4产生显著性影响。尚需进一步的研究证明。     

细胞色素P450—3A4相关的药物相互作用

目的：综述与细胞色素P4503A4相关的药物相互作用。方法：检索Medline和中国药学文摘。结果：发现多种由CYP3A4催化代谢的药物之间可以竞争药物代谢酶,引起药物相互作用,CYP3A4的抑制剂和诱导剂均可以抑制或诱导CYP3A4催化代谢的药物代谢。导致有益或不良的药物相互作用。结论：CYP3A4催化代谢的药物联合使用,特别是CYP3A4抑制剂与底物联合使用时,可能因为抑制了药物的代谢而导致严重的药物不良反应。     

Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity.

With juices of grapefruit and related fruits, possible relationships between contents of six different furanocoumarins and extents of inhibition of microsomal CYP3A activity have been studied in vitro. Microsomal CYP3A-mediated testosterone 6beta-hydroxylation was inhibited by the addition of a fruit juice (2.5%, v/v) from eight different grapefruit sources, two sweeties, three pomelos, and one sour orange, whereas no clear inhibition was observed with two sweet orange juices. The inhibitory component in grapefruit juice resides mainly in the precipitate rather than in the supernatant after centrifugation. Higher amounts of (R)-6',7'-dihydroxybergamottin (DHB) were distributed in the supernatant, whereas GF-I-1, GF-I-2, GF-I-4, and the newly isolated GF-I-5 and GF-I-6 were detected predominantly in the precipitate. Mixing of five representative furanocoumarins at their detectable levels in grapefruit juice reproduced roughly the inhibitory potencies of grapefruit juice, but omission of any of the components resulted in decreased potencies. These results suggested that all the major furanocoumarins contributed to the CYP3A inhibitory properties of grapefruit juice. Furthermore, all six furanocoumarins showed stronger CYP3A inhibitory potencies after preincubation in the presence of NADPH, suggesting that both competitive and mechanism-based inhibition occur in a grapefruit juices-drug interaction.     

Inhibitory effects of fruit juices on CYP3A activity.

There have been very limited reports on the effects of commercial fruit juices on human CYP3A activity. Therefore, the inhibitory effects of readily available commercial fruit juices on midazolam 1'-hydroxylase activity, a marker of CYP3A, were evaluated in pooled human liver microsomes. The fruit juices investigated were black raspberry, black mulberry, plum, and wild grape. White grapefruit, pomegranate, and orange juice were used as positive and negative controls. The black mulberry juice showed the most potent inhibition of CYP3A except for grapefruit juice. The inhibition depended on the amount of a fruit juice added to the incubation mixture. The inhibitory potential of human CYP3A was in the order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry. The IC(50) values of all fruit juices tested were reduced after preincubation with microsomes in the presence of the NADPH-generating system, suggesting that a mechanism-based inhibitory component was present in these fruit juices, as in the case of grapefruit. The results suggest that, like grapefruit juice, commercial fruit juices also have the potential to inhibit CYP3A-catalzyed midazolam 1'-hydroxylation. Therefore, in vivo studies investigating the interactions between fruit juices such as black mulberry and wild grape and CYP3A substrates are necessary to determine whether inhibition of CYP3A activity by fruit juices is clinically relevant.     

Comparative evaluation of 12 immature citrus fruit extracts for the inhibition of cytochrome P450 isoform activities

In a previous study we found that 50% ethanol extracts of immature fruits of Citrus unshiu (satsuma mandarin) have anti-allergic effects against the Type I, II and IV allergic reactions. However, many adverse interactions between citrus fruit, especially grapefruit juice, and drugs have been reported due to the inhibition of cytochrome P450 (CYP) activities. The purpose of this study was to examine the competitive inhibitory effects of extracts from immature citrus fruit on CYP activity. Extracts were prepared from 12 citrus species or cultivars, and were tested against three kinds of major CYPs, CYP2C9, CYP2D6 and CYP3A4, in human liver microsomes. We also estimated the amounts of flavonoids (narirutin, hesperidin, naringin and neohesperidin) and furanocoumarins (bergapten, 6',7'-dihydroxybergamottin and bergamottin) in each extract using HPLC. Citrus paradisi (grapefruit) showed the greatest inhibition of CYP activities, while Citrus unshiu which has an antiallergic effect, showed relatively weak inhibitory effects. Extracts having relatively strong inhibitory effects for CYP3A4 tended to contain higher amounts of naringin, bergamottin and 6',7'-dihydroxybergamottin. These results, providing comparative information on the inhibitory effects of citrus extracts on CYP isoforms, suggest that citrus extracts containing high levels of narirutin and hesperidin and lower levels of furanocoumarins such as C. unshiu are favorable as antiallergic functional ingredients.     

Inhibitory effects of citrus fruits on cytochrome P450 3A (CYP3A) activity in humans

The capacities of citrus fruits to inhibit midazolam 1'-hydroxylase activity of cytochrome P450 3A (CYP3A) expressed in human liver microsomes were evaluated. Eight citrus fruits such as ama-natsu, banpeiyu, Dekopon, hassaku, hyuga-natsu, completely matured kinkan (Tamatama), takaoka-buntan and unshu-mikan were tested. We also examined the inhibition of CYP3A activity by grapefruit (white) and grapefruit juice (white, Tropicana-Kirin). The addition of a fruit juice prepared from banpeiyu, hassaku, takaoka-buntan or Tamatama caused the inhibition of the microsomal CYP3A activity. The inhibition depended on the amount of a fruit juice added to the incubation mixture (2.5 and 5.0%, v/v). The fruit juice from banpeiyu showed the most potent inhibition of CYP3A. The addition of a banpeiyu juice (5.0%, v/v) resulted in the inhibition of midazolam 1'-hydroxylase activity to about 20% of control without a fruit juice. The elongation of the preincubation period of a fruit juice from banpeiyu (5.0%, v/v) with the microsomal fraction (5 to 15 min) led to the enhancement of the CYP3A inhibition (5% of control). Thus, we discovered ingredients of banpeiyu to be inhibitor(s) or mechanism-based inhibitor(s) of human CYP3A activity, but the inhibitory effects of them were somewhat lower than those of grapefruit.     

Inhibitory effect of natural furanocoumarins on human microsomal cytochrome P450 3A activity

To investigate the possible drug interaction with herbal medicine, furanocoumarin derivatives isolated from several Umbelliferous crude drugs were examined for their inhibitory effects on a typical human drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Most furanocoumarins tested at 0.1 mM reduced microsomal testosterone 6beta-hydroxylation as an index of CYP3A activity to less than 50% of the control. In particular, the dimer and trimer derivatives of furanocoumarins showed striking inhibition, whose potencies were similar to that of a typical CYP3A inhibitor, ketoconazole. Preincubation of dimer types of furanocoumarins increased suppression but not most of the monomer derivatives, suggesting that the inhibition on CYP3A activity was caused by at least plural mechanisms. These results raised the possibility that the furanocoumarin containing herbal medicines may alter pharmacokinetics of co-ingested drugs similar to the case with grapefruit juice.     

Mechanism-based inhibition of recombinant human cytochrome P450 3A4 by tomato juice extract

This study investigates whether tomato juice can inhibit cytochrome P450 (CYP) 3A4-mediated drug metabolism. Three commercially available, additive-free tomato juices, along with homogenized fresh tomato, were analyzed for their ability to inhibit testosterone 6β-hydroxylation activity using human recombinant CYP3A4. Results were compared to that of grapefruit juice. Ethyl acetate extracts of the tomato juices moderately reduced residual activity of CYP3A4 testosterone 6β-hydroxylation activity by 19.3-26.2% with 0-min preincubation. Residual activity was strongly reduced by 69.9-83.5% at 20-min preincubation, a reduction similar to that of grapefruit juice extract, known to contain constituents of mechanism-based inhibitors. One juice extract (tomato juice C) showed irreversible dose- and preincubation time-dependent and partial nicotinamide adenine dinucleotide phosphate (NADPH)-dependent inhibition of CYP3A4 activity. Furthermore, we examined whether the CYP3A4 inhibitory effect of tomato juice was substrate dependent by examining midazolam 1'-hydroxylation activity and nifedipine oxidation activity, in addition to testosterone 6β-hydroxylation activity. Tomato juice showed a potent inhibitory effect on nifedipine oxidation activity, which was comparable to that on testosterone 6β-hydroxylation activity; however, it showed a weak inhibitory effect on midazolam 1'-hydroxylation activity. We conclude that tomato juice contains one or more mechanism-based and competitive inhibitor(s) of CYP3A4. Additionally, significant CYP3A4 inhibitory activity did not result from lycopene, a major compound in tomato. Although the active compound was uncertain, a strong CYP3A4 inhibitory activity was observed in other solanaceous plants, i.e., potato, eggplant, sweet pepper, and capsicum. Therefore, responsible compounds in tomato are likely commonly shared among solanaceous vegetables.     

Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines

INTRODUCTIONFuranocoumarins are minor constituents in plants,belonging to Umbelliferae, Rutaceae, Moraceae, andLeguminosae. Some naturally occurring methoxy de-rivatives of furanocoumarins have been applied clinically,coupled with sunbathing, to cure dermatological dis-eases for more than 2000 years, and their confirmedphotosensitizing properties have led to the developmentof a modern medical principle, photochemotherapy[1].On the other hand, some plants containing furano-coumarins are …     

Drug interaction potentials among different brands of grapefruit juice

The discrepancy of drug-interaction potential among different brands of grapefruit juice was estimated based on inhibition of CYP3A activity caused by furanocoumarin derivatives in the grapefruit juice. Heat treatment of the grapefruit juice at 95 degrees C for 1 h was utilized to degrade the furanocoumarins. Initial velocity of testosterone 6beta-oxidation using human liver microsomes was determined as an indicator of the CYP3A activities. Changes in the velocities of the reaction mixture were observed when 10% of each brand of untreated grapefruit juice or heat-treated grapefruit juice was added. The differences in the velocities between untreated and heat-treated grapefruit juice were defined as the potentials of furanocoumarin-caused CYP3A-inhibitions.     

Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine

Objective: Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine. Method: Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h. Results: G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes. Conclusions: This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited.     

Effects of citrus fruit juices on cytotoxicity and drug transport pathways of Caco-2 cell monolayers

The aim of this study was to correlate the taxonomy of grapefruit, pummelo, orange, lime and lemon with fruit juice-mediated cytotoxicity, modulation of epithelial permeability and P-glycoprotein (P-gp)-mediated efflux using 0-50% juice concentrations. Lime and lemon juices at 30% enhanced the absorption of [14C]-mannitol across Caco-2 cell monolayers by six- and eight-fold, respectively, but grapefruit and pummelo juices did not modulate the paracellular [14C]-mannitol transport even at 50%. Orange juice at 30% increased mannitol absorption to a comparable level as lime juice, but had minimal effects on TEER. All five juices did not modulate the passive diffusional pathway as exemplified by their negligible effects on [3H]-propranolol absorption. Grapefruit, pummelo and orange juices showed P-gp inhibitory activity by reducing rhodamine-123 (R-123) efflux and elevating R-123 cellular accumulation, but lime and lemon juices did not. Lime and lemon juices at >or=30% were cytotoxic towards Caco-2 cells. Grapefruit and pummelo juices at 10% did not affect Caco-2 cell viability, but they enhanced cell growth at concentrations of >or=30%. Orange juice increased cell viability only at lower concentrations. On the basis of these data, lime and lemon juices could be regarded as a group distinct from grapefruit and pummelo juices, while orange juice appeared to belong to a bridging group. This grouping was consistent with the categorization of the citrus fruits according to their dominant flavonoid pattern and taxonomy.