Grapefruit Juice and its Constituents Augment Colchicine Intestinal Absorption: Potential Hazardous Interaction and the Role of P-Glycoprotein

Purpose  To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. Methods  Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP–BL and BL–AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6′-7′-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. Results  Colchicine exhibited 20-fold higher BL–AP than AP–BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP–BL permeability was increased and BL–AP was decreased by GFJ in a concentration-dependent manner (IC₅₀ values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6′-7′-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL–AP secretion (IC₅₀ values of 90, 592 and 11.6 μM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. Conclusion  The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.     

Inhibition of P-Glycoprotein Transport Function by Grapefruit Juice Psoralen

Purpose. The grapefruit juice component bergamottin is known to inactivate cytochrome P450 3A4, with grapefruit juice consumption causing increased absorption and enhanced oral bioavailability of many cytochrome P450 3A4 substrates. Many of these substrates are also recognized by the efflux transporter P-glycoprotein. The gene product of MDR1 (multidrug resistance transporter), P-glycoprotein also confers protection against xenobiotics. Methods. Using a whole cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the ability of grapefruit juice components to inhibit the function of this transporter. Results. In a cell line presenting an overexpressed amount of the human transporter, the enzyme exhibited a 40 M IC₅₀ for inhibition by bergamottin. Additionally, using the ATP-hydrolysis assay, we showed that bergamottin increases P-gp-mediated ATP hydrolysis by approximately 2.3 fold with a K_m of 8 M. The concentration for this interaction is similar to that for CYP3A4 inactivation. Conclusions. These results suggest that observed grapefruit juice - drug pharmacokinetic clinical interactions may be due to P-gp inhibition rather than or in addition to CYP3A4 inhibition. Inhibition of P-gp by citrus psoralens could present ways both to enhance bioavailability of therapies without increasing the dose and to diminish drug resistance in refractory cells.     

Grapefruit juice–drug interactions

The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24  h, repeated juice consumption can result in a cumulative increase in felodipine AUC and C_max. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.     

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

Aim

This study examined the effects of grapefruit juice on the new P2Y₁₂ inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.

Methods

In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.

Results

Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C_max) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The C_max and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.

Conclusions

Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.     

Effects of Furanocoumarin Derivatives in Grapefruit Juice on Nifedipine Pharmacokinetics in Rats

Purpose. It has been reported that grapefruit juice (GJ) causes a pharmacokinetic interaction with many drugs after co-ingestion. It is postulated that the substances in GJ may inhibit the first-pass metabolism during the intestinal absorption process. In recent years, several furanocoumarin derivatives that inhibit P450 activity in intestinal microsomes were isolated from GJ. In this study, we report the effects of the furanocoumarin derivatives in GJ on the nifedipine (NFP) pharmacokinetics in rats. Methods. Three furanocoumarin derivatives (bergaptol [BT], bergamottin [BG], and 6,7-dihydroxybergamottin [DHB]) found in GJ were used in this study. Each furanocoumarin was reconstituted in orange juice at the same concentration as in the GJ. Two milliliters of each sample was administered into the rat duodenum. After 30 min, NFP was intraduodenally administered at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by HPLC. Results. A significant increase in the AUC of NFP was observed only in the rats administered BG; 1.5 times that of the control group. The result was quite identical with that of the group that was administered GJ. BT and DHB had no significant effects on the NFP pharmacokinetics. Conclusions. The results strongly suggested that BG in GJ might be the substance that elevates the NFP plasma concentrations.     

Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man

Aims Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.
Methods After an overnight fast, eight healthy volunteers were treated with either 400  ml grapefruit juice or water before intravenous (12  mg) or oral saquinavir (600  mg) was administered. Serial blood samples were obtained over the following 24  h and standardized meals were served 5 and 10  h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.
Results The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76±96 (water, mean (s.d.) to 114±70 (μg  l⁻¹  h (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.
Conclusions The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.     

Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

AIMS: Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. RESULTS: Grapefruit juice increased the area under the plasma concentration-time curves from 0 to 24 h [AUC(0-24)] of simvastatin 3.6-fold (range 1.8-6.0-fold; P < 0.01) and that of simvastatin acid 3.3-fold (range 2.1-5.6-fold; P < 0.01), respectively. The peak concentrations (C(max)) of simvastatin and simvastatin acid were increased 3.9-fold (range 2.3-9.3-fold; P < 0.01) and 4.3-fold (range 2.7-7.9-fold; P < 0.01) by grapefruit juice. CONCLUSIONS: Even one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol-lowering effect and the risk of adverse effects of simvastatin.     

Effects of grapefruit juice on the pharmacokinetics of acebutolol

AIMS: We aimed to investigate effects of grapefruit juice on acebutolol pharmacokinetics. METHODS: In a randomized cross-over study, 10 healthy subjects ingested 200 mL grapefruit juice or water three times daily for 3 days and twice on day 4. On day 3, each subject ingested 400 mg acebutolol with grapefruit juice or water. The concentrations of acebutolol and its metabolite diacetolol were measured in plasma and urine up to 33 h. RESULTS: Grapefruit juice decreased the peak plasma concentration (Cmax) of acebutolol by 19% from 872 +/- 207 ng mL(-1) to 706 +/- 140 ng mL(-1) (95% CI on the difference -306, -26.4; P < 0.05), and the area under the concentration time curve (AUC(0-33 h)) by 7%, from 4498 +/- 939 ng mL(-1) h to 4182 +/- 915 ng mL(-1) h (95% CI -609, -23.0; P < 0.05). The half-life (t1/2) of acebutolol prolonged from 4.0 to 5.1 h (P < 0.05). The time to peak concentration and the amount of acebutolol excreted into urine (Ae) were unchanged. The Cmax, AUC(0-33 h), and Ae of diacetolol were decreased by 24% (P < 0.05), 18% (P < 0.05), and 20% (P < 0.01), respectively, by grapefruit juice. CONCLUSION: Grapefruit juice caused a small decrease in the plasma concentrations of acebutolol and diacetolol by interfering with gastrointestinal absorption. The interaction between the grapefruit juice and acebutolol is unlikely to be of clinical significance in most of the patients.     

Clozapine Drug–Drug Interactions: A Review of the Literature

Clozapine is often used in combination with other medications. To date, there has been no comprehensive review of drug–drug interactions involving clozapine. This review summarizes published reports of suspected drug–drug interactions, and assesses their clinical significance. A computerized search was conducted using MEDLINE (1975–1996) to retrieve all reports of adverse events associated with the concurrent use of clozapine and other agents. Forty-three reports involving 19 different drugs were evaluated. Clozapine appeared to be involved in pharmacokinetic and pharmacodynamic interactions when prescribed concurrently with most major classes of therapeutic agents. In general, the addition of other medications with similar pharmacological effects or side-effects to clozapine may enhance these effects in an additive or possibly synergistic manner. The selective serotonin reuptake inhibitor fluvoxamine was involved in the most thoroughly documented pharmacokinetic interactions, while a number of reports were found implicating various benzodiazepines in apparent pharmacodynamic interactions. No clozapine–drug combination is absolutely contraindicated, but some members of a given therapeutic class may pose less risk than others when used concurrently with clozapine. © 1997 John Wiley & Sons, Ltd.     

门诊处方口服药物相互作用审查与分析

目的:通过对本院门诊处方中口服药物相互作用的审查,对出现的问题进行分析,为临床合理用药提供参考依据.方法:使用美康公司的药物相互作用审查系统对我院2004年6月份5天的2 263张门诊处方进行审查.结果:2 263张处方中,共有197张处方存在潜在的药物相互作用,占审查处方总数的8.70%,可能发生潜在药物相互作用的前5位药物分别为地高辛、氨茶碱、小儿麻黄止咳合剂、强的松、安体舒通,而按药物分类进行统计,前5位分别是心血管系统用药、呼吸系统用药、利尿药、解热镇痛及抗痛风药、抗感染药.结论:对处方中药物相互作用进行审查,发现存在问题,有助于减少药物不良反应,提高临床合理用药水平.     

某院艾滋病住院患者常用中成药与HIV抗病毒药物潜在相互作用分析

摘 要 目的：调查艾滋病住院患者中成药使用情况,并探讨基于细胞色素P450酶(CYP450)以及P糖蛋白（P gp）与HIV抗病毒药物的潜在药物相互作用。方法: 统计2016年1～12月我院艾滋病区中成药使用种类和频度;查阅文献,分析常用中成药或其活性成分对CYP450及P gp活性的影响;归纳一线HIV抗病毒药物对CYP450及P gp的影响;分析中西药潜在相互作用。结果: 艾滋病区2016年DDDs排名前5的中成药分别为痰热清注射液、地榆升白片、注射用血塞通、丹参滴注液、喜炎平注射液;其中,痰热清注射液、丹参滴注液、喜炎平注射液抑制CYP3A4活性,联用可能会增加洛匹那韦、齐多夫定、依非韦伦和奈韦拉平的血药浓度;注射用血塞通抑制P gp底物外排、丹参滴注液降低P gp的表达,与洛匹那韦、齐多夫定、奈韦拉平联用时,可能会影响其转运的过程。结论: 中成药与HIV抗病毒药物的药物相互作用理论上是存在的,临床意义需进一步研究。     

Potential Beneficial Metabolic Interactions Between Tamoxifen and Isoflavones via Cytochrome P450-mediated Pathways in Female Rat Liver Microsomes

PURPOSE: This study aims to evaluate a cytochrome P450-based tamoxifen-isoflavone interaction and to determine the mechanisms responsible for inhibitory effects of isoflavones (e.g., genistein) on the formation of alpha-hydroxytamoxifen. METHODS: Metabolism studies were performed in vitro using female rat liver microsomes. The effects of genistein and an isoflavone mixture on tamoxifen metabolism and the inhibition mechanism were determined using standard kinetic analysis, preincubation, and selective chemical inhibitors of P450. RESULTS: Metabolism of tamoxifen was saturable with Km values of 4.9+/-0.6, 14.6+/-2.2, 25+/-5.9 microM and Vmax values of 34.7+/-1.4, 297.5+/-19.2, 1867+/-231 pmol min(-1) mg(-1) for a-hydroxylation, N-desmethylation, and N-oxidation, respectively. Genistein (25 microM) inhibited alpha-hydroxylation at 2.5 microM tamoxifen by 64% (p < 0.001) but did not affect the 4-hydroxylation, N-desmethylation, and N-oxidation. A combination of three (genistein, daidzein, and glycitein) to five isoflavones (plus biochanin A and formononetin) inhibited tamoxifen alpha-hydroxylation to a greater extent but did not decrease the formation of identified metabolites. The inhibition on alpha-hydroxylation by genistein was mixed-typed with a Ki, value of 10.6 microM. Studies using selective chemical inhibitors showed that tamoxifen alpha-hydroxylation was mainly mediated by rat CYP1A2 and CYP3A1/2 and that genistein 3'-hydroxylation was mainly mediated by rat CYP1A2, CYP2C6 and CYP2D1. CONCLUSIONS: Genistein and its isoflavone analogs have the potential to decrease side effects of tamoxifen through metabolic interactions that inhibit the formation of a-hydroxytamoxifen via inhibition of CYP1A2.     

Fruit juice inhibition of uptake transport: a new type of food-drug interaction

A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume–effect relationship study using a normal juice amount halved average fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.     

常用降压药物的相互作用

高血压是心脑血管疾病的主要危险因素之一,安全和有效的控制血压是降低心脑血管疾病风险必不可少的措施。本文简单介绍了常用的5种降压药物（利尿剂、钙拮抗剂、β肾上腺素受体阻滞剂、血管紧张素转换酶抑制剂、血管紧张素Ⅱ受体阻滞剂）联合应用的原则,重点介绍这5种降压药物联合应用时可能产生的药物相互作用,以及与其它非降压药物联合应用时可能产生的药物相互作用。旨在引起临床关注联合治疗中药物的相互作用和对用药安全产生的影响。     

Naringin does not alter caffeine pharmacokinetics, energy expenditure, or cardiovascular haemodynamics in humans following caffeine consumption

1. Naringin, a grapefruit constituent interacts with many medications including caffeine, a popular weight loss supplement. The purpose of the current study was to identify changes in caffeine pharmacokinetics, resting energy expenditure (REE), oxygen consumption (VO(2)) and respiratory exchange ratio (RER) after an acute dosage of caffeine and naringin. 2. Using a double-blinded, counterbalanced design, REE, VO(2), and RER were measured before and systematically for 8 h after a single dosage of caffeine (CAF, 200 mg) with and without naringin (100 mg (CN100) or 200 mg (CN200)) in 10 apparently healthy individuals. A standardized meal was provided following 240-minute measurements (400 kcals; 35 g carbohydrate; 27 g protein; 7 g fat). 3. Caffeine, CN100, CN200 did not alter VO(2) or VO(2) area under the curve (137 301 +/- 8318, 139 729 +/- 9300, 134 297 +/- 8318, mL/480 min). Resting energy expenditure (k/cals) was 10.0 +/- 1.4% higher with CAF versus CN200 (6.0 +/- 1.4%) and CN100 (6 +/- 1.5%) at 240 min (P = 0.07) which was then negated following a standardized meal. Percent change in RER from pre to 240 min and pre to 480 min was not different between the CAF, CN100, or CN200 (-0.2 +/- 1.7%, 1.7 +/- 1.7%, -2.8 +/- 1.9%). 4. Although caffeine alone suggests a trend of increased REE, the results of the present study indicate that concurrent consumption of caffeine with naringin in acute dosages does not affect RER, VO(2), and prevents the increase of REE in adult humans. The results suggest that the interaction of grapefruit juice and caffeine may be due to constituents of grapefruit juice other than naringin or in addition to naringin.     

Inhibition of CYP3A4 by 6′,7′‐dihydroxybergamottin in human CYP3A4 over‐expressed hepG2 cells

Objectives We previously established HepG2‐GS‐3A4, a cell line from hepatoblastoma with overexpression of human CYP3A4 and glutamine synthetase (GS). We further reported that these cells can be applied for screening inhibitors of CYP3A4 in vitro. The purpose of this study was to determine whether our CYP3A4‐overexpresed cell could be applied to evaluate mechanisms of CYP3A4 inhibition by 6′,7′‐dihydroxybergamottin (DHB), which is one of the major furanocoumarins in grapefruit juice, by using these cells. Methods Nifedipine oxidation, activity and protein expression of NADPH‐cytochrome reductase (POR) of HepG2‐GS‐3A4 cell were measured. CO‐binding spectrumassay in microsomal fraction of the cells was also evaluated. Key findings DHB and ketoconazole, a well‐known inhibitor of CYP3A4, inhibited nifedipine oxidation in a concentration‐dependent manner. DHB at a concentration of 3.0 µm , sufficient to inhibit the nifedipine oxidation, decreased POR activity; however, ketoconazole at a concentration of 0.9 µm , sufficient to inhibit the oxidation, did not affect the activity. The expression of POR protein in HepG2‐GS‐3A4 cells was not changed by either DHB or ketoconazole. The expression of CYP3A4 mRNA and protein was not changed by the addition of DHB or ketoconazole. DHB also reduced the absorption rate at 450 nm in a CO‐binding spectrum assay without alteration of the wavelength of maximum absorption. The mean absorption value at 450 nm slightly decreased with ketoconazole; however, the difference was not significant. Conclusions We concluded that inhibition of CYP3A4 activity by DHB includes the inhibition of POR activity. HepG2‐GS‐3A4 might be a good tool to evaluate the mechanisms.     

Modulation of Digoxin Transport Across Caco-2 Cell Monolayers by Citrus Fruit Juices: Lime,Lemon, Grapefruit,and Pummelo

Purpose. To evaluate the effects of fresh lime, lemon, grapefruit, and pummelo juices on the transport of digoxin, a P-glycoprotein (P-gp) substrate, in Caco-2 cell monolayers. Methods. Bidirectional [³H]-digoxin fluxes across confluent Caco-2 cell monolayers were determined in 0-50% fruit juices at pH 7.4. Verapamil HCl (100 M) served as positive control. Juice toxicity was evaluated by the 3-(4,5 dimethylthiazolyl-2)-2,5-diphenyl- tetrazolium bromide assay. Results. Apical-to-basal (A-to-B) digoxin flux was enhanced by 50% fruit juice in the order of lemon > lime > pummelo > grapefruit. The four fruit juices could be divided into two groups based on their effects on transepithelial electrical resistance (TEER), viability, and digoxin transport activity of the Caco-2 cells. Grapefruit and pummelo juices produced similar digoxin transport profiles that were characteristic of those observed with P-gp inhibitors. Both juices decreased net digoxin efflux by 1.2 U per 10% increase in juice concentration and had a propensity to increase cellular TEER at high concentrations (>30%). However, cellular TEER and viability decreased with increasing concentration of lime and lemon juices. Both juices also produced similar digoxin transport profiles, the A-to-B and B-to-A digoxin P_app increasing with increasing juice concentration above 5%. Net digoxin efflux was 30% of control value and relatively independent of juice concentration. These results paralleled the groupings of the four fruits according to their prominent flavonoid pattern and taxonomy. Conclusion. The effects of lime, lemon, grapefruit, and pummelo juices on the TEER, viability, and digoxin transport activity of the Caco-2 cells appeared to be dependent on the dominant flavonoid pattern and taxonomy of the citrus fruits.     

慢性阻塞性肺疾病住院患者药物相互作用调查

目的:了解慢性阻塞性肺疾病住院患者药物治疗及不良相互作用的发生情况。方法:从清华大学第一附属医院2006年10月～2007年2月所有被诊断为慢性阻塞性肺疾病的住院病历中随机抽取54份,调查患者的基本情况及用药情况。结果:慢性阻塞性肺疾病住院患者超过20%的时间应用8种以上药物,70%的患者存在不良相互作用。结论:该院慢性阻塞性肺疾病住院患者用药种类过多,产生不良相互作用情况较多,应采取干预措施。     

Influence of grapefruit juice on pharmacokinetics of triptolide in rats grapefruit juice on the effects of triptolide

1.?Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp).

2.?This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats.

3.?The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data.

4.?The results indicated that coadministration of GFJ could increase the systemic exposure of triptolide significantly, including area under the curve (828.58?±?79.72 versus 541.53?±?45.23?ng·h/mL) and maximum plasma concentration (273.58?±?27.98 versus 193.67?±?10.08?ng/mL). The apparent permeability of triptolide across the Caco-2 cell transwell model increased significantly with the pretreatment of GFJ (from 1.62?±?0.25?×?10^?6 to 2.51?±?0.41?×?10^?6 cm/s), and the metabolic stability of triptolide was also increased from 32.6?±?5.1 to 52.5?±?7.8?min with the pretreatment of GFJ, and the difference was significant (p?5.?In conclusion, GFJ could increase the systemic exposure of triptolide in rats, when GFJ and triptolide was coadministered, and it might work mainly through increasing the absorption of triptolide by inhibiting P-gp, or through slowing down the metabolism of triptolide in rat liver by inhibiting the activity of CYP3A4.