中药有效成分对细胞色素P450酶的抑制活性评价

目的评价10个中药有效成分对人肝微粒体5种CYP同工酶(CYP1A2、2C9、2C19、2D6和3A4)的抑制活性,为临床合理用药提供参考。方法在混合人肝微粒体孵育体系中,分别以非那西丁O-脱乙基、甲苯磺丁脲4-羟基化、奥美拉唑5-羟基化、右美沙芬O-脱甲基化和咪达唑仑1'-羟基化反应为5种同工酶代谢活性的标志,用阳性抑制剂对试验体系进行验证。应用LC-MS检测受试物对探针底物代谢产物生成量的影响,得到抑制率并计算IC50。结果柚皮素是CYP2C19的强抑制剂和1A2的中等抑制剂(IC50为0.43和4.79μmol.L-1)。异鼠李素是CYP1A2、2C9和2C19的中等抑制剂,IC50分别为5.36、1.40和3.28μmol.L-1。大黄酸对CYP1A2和3A4的IC50分别为8.32和2.50μmol.L-1,为中等抑制剂。喜树碱是CYP2C9和2C19的中等抑制剂(IC50为2.01和2.48μmol.L-1)。金雀花碱、小檗碱和齐墩果酸抑制CYP2C9、2D6和2C19的IC50分别为8.13、4.69和3.56μmol.L-1,为中等抑制剂。结论柚皮素、异鼠李素、金雀花碱、盐酸小檗碱、喜树碱、大黄酸和齐墩果酸对CYP同工酶有不同程度的抑制作用,在临床应用时应注意可能的药-药相互作用。

Optimizing hepatitis C virus treatment through pharmacist interventions: Identification and management of drug-drug interactions

To quantify drug-drug-interactions (DDIs) encountered in patients prescribed hepatitis C virus (HCV) treatment, the interventions made, and the time spent in this process.METHODSAs standard of care, a clinical pharmacist screened for DDIs in patients prescribed direct acting antiviral (DAA) HCV treatment between November 2013 and July 2015 at the University of Colorado Hepatology Clinic. HCV regimens prescribed included ledipasvir/sofosbuvir (LDV/SOF), paritaprevir/ritonavir/ombitasvir/dasabuvir (OBV/PTV/r + DSV), simeprevir/sofosbuvir (SIM/SOF), and sofosbuvir/ribavirin (SOF/RBV). This retrospective analysis reviewed the work completed by the clinical pharmacist in order to measure the aims identified for the study. The number and type of DDIs identified were summarized with descriptive statistics.RESULTSSix hundred and sixty four patients (83.4% Caucasian, 57% male, average 56.7 years old) were identified; 369 for LDV/SOF, 48 for OBV/PTV/r + DSV, 114 for SIM/SOF, and 133 for SOF/RBV. Fifty-one point five per cent of patients were cirrhotic. Overall, 5217 medications were reviewed (7.86 medications per patient) and 781 interactions identified (1.18 interactions per patient). The number of interactions were fewest for SOF/RBV (0.17 interactions per patient) and highest for OBV/PTV/r + DSV (2.48 interactions per patient). LDV/SOF and SIM/SOF had similar number of interactions (1.28 and 1.48 interactions per patient, respectively). Gastric acid modifiers and vitamin/herbal supplements commonly caused interactions with LDV/SOF. Hypertensive agents, analgesics, and psychiatric medications frequently caused interactions with OBV/PTV/r + DSV and SIM/SOF. To manage these interactions, the pharmacists most often recommended discontinuing the medication (28.9%), increasing monitoring for toxicities (24.1%), or separating administration times (18.2%). The pharmacist chart review for each patient usually took approximately 30 min, with additional time for more complex patients.CONCLUSIONDDIs are common with HCV medications and management can require medication adjustments and increased monitoring. An interdisciplinary team including a clinical pharmacist can optimize patient care.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.

Identification of the Interaction between P-Glycoprotein and Anxa2 in Multidrug-resistant Human Breast Cancer Cells

Objective To explore the interaction of Anxa2 with P-Glycoprotein （P-gp） in the migration and invasion of the multidrug-resistant （MDR） human breast cancer cell line MCF-7/ADR. Methods A pair of short hairpin RNA （shRNA） targeting P-gp was transfected into MCF-7/ADR cells, and monoclonal cell strains were screened. The expression of P-gp was detected by Western blot. Transwell chambers were used to observe the cell migration capacity and invasion ability. The interaction between P-gp and Anxa2 was examined by immunoprecipitation and immunofluorescence confocal microscopy analyses. Results P-gp expression was significantly knocked down, and there were notable decreasing trends in the migration and invasion capability of MDR breast cancer cells （P〈0.05）. There was a close interaction between Anxa2 and P-gp. Conclusions MCF-7/ADR is an MDR human breast cancer cell line with high migration and invasion abilities. The knockdown of P-gp notably impaired the migration and invasion abilities of the tumor cells. The interaction of Anxa2 with P-pg may play an important role in time enhanced invasiveness of MDR human breast cancer cells.

5种抗肿瘤中药注射液对CYP3A4酶代谢的影响

目的以睾酮为探针药物,于体外研究5种抗肿瘤中药注射液(康艾、消癌平、华蟾素、参附、注射用香菇多糖)对大鼠细胞色素P4503A4(CYP3A4)亚型酶活性的影响。方法采用大鼠肝微粒体体外孵育法,用HPLC法测定5种抗肿瘤中药注射液孵育体系中6β-羟基睾酮的生成量,反映其对CYP3A4酶活性的影响。结果与空白组相比,参附对CYP3A4酶活性无明显影响;华蟾素对CYP3A4有诱导作用;康艾、香菇多糖、消癌平对CYP3A4有抑制作用,消癌平的IC50为0.69%。结论在临床上经CYP3A4代谢的药物联合应用时,应警惕华蟾素、康艾、香菇多糖、消癌平潜在的药-药相互作用。

4种抗肿瘤中药注射液对大鼠细胞色素P4503A4亚型酶活性的影响

目的以睾酮为探针药物体外研究抗肿瘤中药注射液榄香烯、康莱特、鸦胆子油、艾迪对大鼠细胞色素P4503A4(CYP3A4)亚型酶活性的影响。方法用大鼠肝微粒体体外孵育法,用高效液相色谱法测定4种抗肿瘤中药注射液在孵育体系中6β-羟基睾酮(6-OHTS)生成量,反映其对CYP3A4酶活性的影响。结果与空白组相比,榄香烯对CYP3A4酶活性无明显影响;康莱特与艾迪对CYP3A4有诱导作用;鸦胆子油乳对CYP3A4有抑制作用,半数抑制率IC50值为0.78%。结论临床上在与经CYP3A4代谢的药物联合应用时,应警惕康莱特、艾迪及鸦胆子油乳潜在的药-药相互作用。

药物代谢酶特异性探针底物的研发与应用进展

人体内分布数百种结构多样、功能各异的药物代谢酶,其表达和功能易受遗传和环境因素的影响,导致其在不同人种、个体及组织中的分布都不尽相同。特异性探针底物作为药物代谢酶活性表征的关键工具分子,其在新药发现、药-药相互作用评价、临床药理学及精准医学检测等领域具有重要的应用价值。围绕人体分布的重要药物代谢酶,综述其特异性探针底物的设计研发及生物医学应用进展,以期为药物代谢酶的精准检测及相关应用研究提供参考。

Reduction of Praziquantel Elimination by Cimetidine in Rats

The effect of cimetidine on the elimination of praziquantel(PQT)in rats was studied. The results showed that cimetidine 100 mg/kg,ip 2 reduced the clearances of intravenous and oral PQT by 60 and 69 percent respectively.Cimetidine also markedly reduced liver blood flow of rats(a reduction of 58%)and inhibited PQT metabolism in hepatic microsomes of rats(an inhibition of 55%). The reduction in clearance of intravenous PQT could be attributed to the result of cimetidine lowering liver blood flow,whereas the reduction in clearance of oral PQT might be related mainly to the inhibition of cimetidine on the activity of hepatic drug-metabolizing enzymes.

Statins for primary cardiovascular prevention in the elderly

The elderly population is increasing worldwide, with subjects 〉 65 years of age constituting the fastest-growing age group. Furthermore, the elderly face the greatest risk and burden of cardiovascular disease mortality and morbidity. Although elderly patients, particularly those older 〉 75, have not been well represented in randomized clinical trials evaluating lipid-lowering therapy, the available evidence supporting the use of statin therapy in primary prevention in older individuals is derived mainly from subgroup analyses and post-hoc data. On the other hand, elderly patients often have multiple co-morbidities that require a high number of concurrent medications; this may increase the risk for drug-drug interactions, thereby reducing the potential benefits of statin therapy. The aim of this review was to present the relevant literature regarding statin use in the elderly for theft primary cardiovascular disease, with the associated risks and benefits of treatment.

Ceritinib： From Synthesis to Clinical Applications

Lung cancer is the major cause of cancer-related mortality, accountingfor over one quarter of cancer deaths. Lung cancers are generally divided into two main categories： SCLC （small cell lung cancer） and NSCLC （non-small cell lung cancer）. NSCLC accounts for approximately 85% of all lung cancers. ALK （anaplastic largecell kinase） gene rearrangements are identified and targeted resulting in promising response rates for NSCLC in early studies. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib （the first-generation ALK inhibitor）-resistant patients. In this paper, the synthesis, pharmacodynamics, pharmacokinetics, therapeutic trials, adverse events and drug-drug interactions are briefly overviewed in order to make more scholars, medical workers and patients have a more clear and comprehensive recognition on this drug.

Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells

Objective： The combination effect of Piperbetle （PB） and 5-fluorouracil （5-FU） in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods： HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography （HPLC） was performed to exclude any possible chemical interaction between the compounds. Results： In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose （IC^0 12.5 pmol/L） and a shorter time （24 h） in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. Conclusions： In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.

Herb-drug enzyme-mediated interactions and the associated experimental methods： a review

OBJECTIVE: To review the interactions between herbs and widely used drugs and summarize the associated experimental methods.METHODS: Definite herb-drug interactions were obtained by searching Pub Med, other large overseas databases and summarizing new researches from China. We summarize some methods to assess the interaction between herbs and drugs involving microsomal, cell culture and animal experiments, and clinical trials, classifying this method as single ingredient herbs, crude herb extracts, andherbal formulae.RESULTS: Many herbs interact with drugs through a complex cytochrome P450 and/or P-glycoprotein mechanism. Herb-induced enzyme inhibition and/or induction may result in enhanced and / or decreased plasma, tissue, urine and bile drug concentrations, leading to a change in a drug's pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects. Use of an appropriate method for comprehensively assessing herb-drug interactions can minimize clinical risks. Different methods were used by researchers to assess the pharmacological changes of drugs in vivo and in vitro and the mechanisms of the interactions from microsomal, cell culture and animal experiments, and clinical trials are discussed in this review.CONCLUSION: Co-medication with herbs can result in changes in pharmacological effects of many drugs. This review describes the assessment of single-ingredient herbs, crude herb extracts, and herbal formulae. When choosing a research method to investigate herb-drug interactions, the properties of the drugs and herbs should be considered.

Effects of Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule on the pharmacokinetics of clopidogrel active metabolite in rats

In the present study, we aimed to examine the effects of Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule on the pharmacokinetics of clopidogrel active metabolite（CAM）. The traditional Chinese medicines（TCMs） Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule are widely used to treat cardiovascular disease in China. They are often prescribed in combination with clopidogrel, a common anti-platelet Western drug. We investigated the influence of the four TCMs on CAM pharmacokinetics following administration at human dose in rats. Pharmacokinetic parameters were determined following oral（PO） administration of clopidogrel（7.5 mg/kg） with or without Rong Shuan capsule（75 mg/kg, PO）, Xue Zhi Kang capsule（60 mg/kg, PO）, Xin Yuan capsule（120 mg/kg, PO）, or Songling Xue Mai Kang capsule（150 mg/kg, PO）. Compared with the animals in the control group, Xue Zhi Kang capsule significantly decreased the area under the plasma concentration-time curve（AUC_（0-t）） of the CAM derivative by 25.4%. However, the t1/2 and Vz/F of CAM derivative were significantly increased by 43.6% and 70.7%, respectively. It was also observed that the pharmacokinetic parameters were altered in groups pretreated with Rong shuan capsule, Xin yuan capsule or Songling Xue mai kang capsule compared with the control group, but not significant. This study indicated that Xue Zhi Kang capsule had an effect on the formation and metabolism of CAM. Therefore, in the beginning of co-administration of Xue Zhi Kang capsule and clopidogrel, the anti-platelet efficacy might be compromised because of the decreased formation of CAM. Otherwise, long-time co-administration might lead to side effects by the prolongation of the t1/2 and Vz/F increase of CAM.

Influence of voriconazole on pharmacokinetics and safety of combined drugs: a systematic review

We performed a systematic review to evaluate pharmacokinetics changes of drugs when concomitantly used with voriconazole, including randomized controlled trials（RCTs）, randomized cross-over trials, self-controlled before-and-after studies, cohort studies and case reports. Literature databases, including Medline, Embase, Cochrane library, were searched to identify eligible studies（until Jan, 2016）. A modified risk of bias tool specially developed in this research was used to evaluate the quality of pharmacokinetic randomized crossover trials and self-controlled before-and-after studies. Cochrane risk of bias tool provided by Cochrane Library and Cochrane Reviewer＇s handbook was used to evaluate the quality of RCTs and non-randomized controlled studies. Pharmacokinetic parameters, such as area under curve（AUC）, Cmin, and Cmax before and after using voriconalzole were collected. Meta-analysis was conducted to synthesize results if possible. Among 41 studies included in our search, 17 were randomized crossover trials, 3 were RCTs, 13 were self-controlled before-and-after study（SBAs）, 1 was cohort studies and 7 were case reports. A total of 12 classes of drugs were involved, including opiates, non-steroidal anti-inflammatory drugs（NSAIDs）, psychopathic drugs, anti-HIV drugs, immunosuppressors, oral contraceptive, digoxin, warfarin, oral hypoglycemic agents, antihypertensive agents, lipid regulating agents and cytotoxic agents. According to our results, the impacts of voriconazole on tilidine, buprenorphine, etoricoxib, meloxicam, venlafaxine, midazolam, zolpidem, etravirine and sirolimus were different from the package insert. Our systematic review provided comprehensive data on the pharmacokinetics changes of drugs when used in combination with voriconazole.

Study on the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats

In the present study,we aimed to investigate the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats.Coadministration of repaglinide（0.5 mg/kg,1 mg/kg and 2 mg/kg） for 7 d significantly increased the AUC0–24 and Cmax of rosuvastatin（P〈0.01）,but dramatically decreased the CL/F of rosuvastatin（P〈0.01） after a single dose of rosuvastatin（10 mg/kg）.There were no obviously changes in the parameters of Tmax and t1/2.Coadministration of repaglinide also decreased the liver distribution of rosuvastatin（P〈0.01）.Coadministration of rosuvastatin（20 mg/kg） for 7 days significantly increased the AUC0–12 and Cmax of repaglinide（P〈0.05）,and decreased the CL/F of repaglinide（P〈0.01） after a single dose of repaglinide（1 mg/kg）.The liver distribution of repaglinide was also decreased（P〈0.01）.Our animal study indicated that repaglinide could significantly affect the pharmacokinetics and liver distribution of rosuvastatin in rats and vice versa.