共查询到20条相似文献,搜索用时 13 毫秒
1.
Reimann G Barthel B Rockstroh JK Spatz D Brockmeyer NH 《International journal of clinical pharmacology and therapeutics》1999,37(11):562-566
OBJECTIVE: To investigate the effects of fusidic acid therapy on the hepatic cytochrome P450 (CYP450) enzyme system. METHODS: Thirty HIV-seropositive L-methadone-substituted i.v. drug abusers (stage CDC/WHO B2 - 3 with CD4+-counts ranging from 65 to 293/microl) were randomized into 3 groups (A - C). Ten patients were treated with fusidic acid 500 mg/day over a period of 14 (group A) or 28 days (group B), respectively. Patients in group C served as a control group and did not receive any medication apart from L-methadone. In order to investigate the hepatic monooxygenase system, pharmacokinetics were determined in all patients before initiation and 14 and 28 days after starting therapy with fusidic acid. The concentration of antipyrine and its 3 main metabolites (norantipyrine (NORA), 4-hydroxyantipyrine (OHA), 3-hydroxymethylantipyrine (HMA)) in plasma and urine were measured by high-performance liquid chromatography (HPLC). RESULTS: No effects on antipyrine pharmacokinetics and pharmacokinetics of antipyrine metabolites were found in group A after 14 days of fusidic acid intake and in the control group without therapy. However, in contrast an activation of the CYP450 enzyme system was observed in group B after 28 days of fusidic acid therapy with an increase of total antipyrine clearance (43.0 +/- 7.62 ml/min to 51.0 +/- 9.03 ml/min) as well as clearances to all metabolites (NORA 7.11 +/- 1.75 to 8.60 +/-2.10 ml/min, OHA 11.5 +/- 2.89 to 14.0 +/- 3.97 ml/min, HMA 4.05 +/- 0.99 to 4.94 +/- 1.27 ml/min). Antipyrine half-life was significantly reduced (12.3 +/- 2.8 h to 9.4 +/- 2.2 h) and some patients developed clinical signs of L-methadone underdosage. CONCLUSIONS: Our results suggest that fusidic acid has a time-dependent activating effect on the CYP450 enzyme system. Especially in treatment of patients who are frequently under multidrug regimens such as HIV-positive patients drug interactions should be taken into consideration. 相似文献
2.
文拉法辛与细胞色素P450酶的相关性研究进展 总被引:1,自引:0,他引:1
文拉法辛是具有5-HT和NE双重再摄取抑制作用的新型抗抑郁药,与文拉法辛代谢密切相关的2种酶是CYP3A4和CYP2D6。CYP2D6将其生物转化为主要的活性代谢产物——O-去甲基文拉法辛(ODV),同时CYP3A4将文拉法辛转化为非活性代谢产物N-去甲基文拉法辛(NDV)。在常规治疗剂量下文拉法辛对于CYP3A4缺乏明显的诱导或抑制作用。而CYP2D6的活性直接影响文拉法辛和ODV的代谢和浓度,由于CYP2D6存在着基因遗传多态性,不同表型有着不同的文拉法辛代谢能力,而慢代谢者更易发生不良反应。研究证实文拉法辛与ODV的浓度比log(VENL/ODV)可作为异常代谢的指标,较简便地发现大多数异常基因型患者。 相似文献
3.
4.
Fleming BD Johnson DL Bond AM Martin LL 《Expert opinion on drug metabolism & toxicology》2006,2(4):581-589
Cytochrome P450 (CYP) enzymes perform crucial functions in humans, including the metabolism of drugs and hormone synthesis. The catalytic reactions performed by these enzymes (typically monoxygenation) require the transfer of electrons. Thermodynamic and mechanistic detail of the electron transfer component of these catalytic processes has been obtained traditionally from potentiometric titrations. More recently, voltammetric approaches (that are inherently simpler and require less sample) have been used. This has been made possible by the creation of biocompatible electrode surfaces at which the P450 enzyme is confined and able to undergo physiologically relevant electron transfer processes. The continuing challenge has been to obtain an in vivo-like enzyme response, and to provide the basis for the creation of an artificial bioprocess in vitro. A powerful instrumental electrochemical method, employing Fourier-transformed large-amplitude ac voltammetry, offers the potential for greater insight and new opportunities to understand the nuances of the electron transfer process. This review highlights several recent advances in the electrochemistry of P450 enzymes rather than providing a comprehensive review of P450 electrochemistry. 相似文献
5.
6.
Santosh Kumar Sreevatsav Adiraju Kiran Shekar John F. Fraser Maree T. Smith 《Drug metabolism reviews》2018,50(2):109-124
For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug–drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population. 相似文献
7.
M. Dostalek J. Jurica J. Pistovcakova M. Hanesova J. Tomandl I. Linhart 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(12):1355-1366
Amphetamine-based drugs, including methamphetamine, are some of the most widely used illegal drugs in the world. Methamphetamine is metabolized by the cytochrome P450s, the latter also being involved in the metabolism of many drugs and other xenobiotics. The effect of methamphetamine pretreatment (10?mg?kg–1, intraperitoneally once daily for 6 days) on the activity of the P450 enzymes was assessed both in the rat isolated perfused liver and in vivo. The rate of 4-hydroxydiclofenac production was significantly enhanced in vivo, indicating a possible stimulatory effect on P4502C6. Similarly, the kinetics of tolbutamide and dextromethorphan in isolated perfused rat liver indicate a significant increase in both P4502C6 and the P4502D subfamily. No significant changes in midazolam kinetic in the isolated perfused rat liver were observed. The potential for methamphetamine to cause drug interactions is of clinical relevance and, therefore, it warrants further investigation. Until further drug interaction experiments are accomplished, the co-administration of drugs with methamphetamine should be conducted with caution. 相似文献
8.
Dostalek M Jurica J Pistovcakova J Hanesova M Tomandl J Linhart I Sulcova A 《Xenobiotica; the fate of foreign compounds in biological systems》2007,37(12):1355-1366
Amphetamine-based drugs, including methamphetamine, are some of the most widely used illegal drugs in the world. Methamphetamine is metabolized by the cytochrome P450s, the latter also being involved in the metabolism of many drugs and other xenobiotics. The effect of methamphetamine pretreatment (10 mg kg-1, intraperitoneally once daily for 6 days) on the activity of the P450 enzymes was assessed both in the rat isolated perfused liver and in vivo. The rate of 4-hydroxydiclofenac production was significantly enhanced in vivo, indicating a possible stimulatory effect on P4502C6. Similarly, the kinetics of tolbutamide and dextromethorphan in isolated perfused rat liver indicate a significant increase in both P4502C6 and the P4502D subfamily. No significant changes in midazolam kinetic in the isolated perfused rat liver were observed. The potential for methamphetamine to cause drug interactions is of clinical relevance and, therefore, it warrants further investigation. Until further drug interaction experiments are accomplished, the co-administration of drugs with methamphetamine should be conducted with caution. 相似文献
9.
《Pharmaceutical biology》2013,51(7):995-1001
AbstractContext: Kanglaite (KLT) is an oily substance extracted from Coix lacryma-jobi Linn. (Cramineae) and has been proved to significantly improve the life span and quality of life of patients, when combined with chemotherapy, radiotherapy, or surgery.Objective: The purpose of this study was to find out whether KLT influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4) by using cocktail probe drugs in vivo.Materials and methods: A cocktail solution at a dose of 5?mL/kg, which contained phenacetin (20?mg/kg), bupropion (20?mg/kg), tolbutamide (5?mg/kg), omeprazole (20?mg/kg), and midazolam (10?mg/kg), was given as oral administration to rats treated with 7?d intraperitoneal injection of KLT. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0 (SPPS Inc., Chicago, IL).Results: In the experiment, there was a statistically significant difference in the t1/2, Cmax, AUC(0–∞), and CL for phenacetin, bupropion, tolbutamide, omeprazole, and midazolam. Our study showed that treatment with multiple doses of KLT had induction effect on rat CYP1A2, while CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activities had been inhibited after multiple doses of KLT treatment.Conclusions: KLT can either induce or inhibit activities of CYP. Therefore, caution is needed when KLT is co-administration with some CYP substrates in clinic, which may result in herb–drug interactions. 相似文献
10.
11.
Porcelli S Fabbri C Spina E Serretti A De Ronchi D 《Expert opinion on drug metabolism & toxicology》2011,7(9):1101-1115
INTRODUCTION: The cytochrome P450 (CYP) enzymes are the major enzymes responsible for Phase I reactions in the metabolism of several substances, including antidepressant medications. Thus, it has been hypothesized that variants in the CYP network may influence antidepressant efficacy and safety. Nonetheless, data on this field are still contradictory. The authors aim to give an overview of the published studies analyzing the influence of CYP highly polymorphic loci on antidepressant treatment in order to translate the acquired knowledge to a clinical level. AREAS COVERED: The authors collected and compared experimental works and reviews published from the 1980s to the present and included in the Medline database. The included studies pertain to the effects of CYP gene polymorphisms on antidepressant pharmacokinetic parameters and clinical outcomes (response and drug-related adverse effects), with a focus on applications in clinical practice. The authors focused mainly on in vivo studies in humans (patients or healthy volunteers). EXPERT OPINION: Great variability in antidepressant metabolism among individuals has been demonstrated. Thus, with the current interest in individualized medicine, several genetic tests to detect CYP variants have been produced. They provide a potentially useful way to anticipate some clinical outcomes of antidepressant treatment, although they will only be extensively used in clinical practice if precise and specific treatment options and guidelines based on genetic tests can be provided. 相似文献
12.
Cytochrome P450 enzyme polymorphisms and adverse drug reactions 总被引:5,自引:0,他引:5
13.
Zhengshuai Chen Jingjie Li Peng Chen Fengjiao Wang Ning Zhang Min Yang 《Xenobiotica; the fate of foreign compounds in biological systems》2016,46(9):850-856
1. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy.2.?We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3′-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions.3.?We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C?>?T in exon 1, two mutations 32120C?>?G and 32245T?>?C in 3′-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype “TTAGGT” was the most prevalent with 0.781.4.?Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs. 相似文献
14.
细胞色素P450氧化还原酶(Cytochrome P450 0xidoreductase,POR)是将电子从NADPH转运至所有肝微粒体的细胞色素P450氧化酶(Cytochrome P450 monooxygenases,CYP)中的唯一供体.药物、类固醇激素等物质的代谢和转化需要CYP参与.POR基因具有遗传多态性,遗传变异可以改变CYP活性,引起P450氧化还原酶缺陷(P450 0xidoreductase deficiency,PORD)、临床药物代谢和反应差异.本文将从POR的结构功能、基因突变引起的疾病及其对酶活性影响三个方面进行论述,总结近年来POR遗传多态性对CYP酶影响的最新研究进展. 相似文献
15.
Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng?hr/ml [interquartile range (IQR) 37.8-64.3 ng?hr/ml] vs 34.9 ng?hr/ml [IQR 21.6-42.2 ng?hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant. 相似文献
16.
Kulthong K Maniratanachote R Kobayashi Y Fukami T Yokoi T 《Xenobiotica; the fate of foreign compounds in biological systems》2012,42(9):854-862
Silver nanoparticles (AgNPs) are increasingly used in various products and consequentially the potential adverse effects associated with exposure to them are of concern. This study investigated the effects of AgNPs on the hepatic drug-metabolizing enzymes of the cytochrome P450 (CYP) families 1, 2 and 3, using both in vitro and in vivo biological assays. AgNPs were orally administered to Sprague-Dawley rats at various concentrations (0-1000 mg/kg body weight/day) for 2 weeks. No effect was found on the plasma levels of ALT, AST and ALP in all treated rat groups, and no significant change in the activities of CYP1A, CYP2C, CYP2D, CYP2E1 and CYP3A was observed for all tested AgNP doses. The results correlated with the observation that no AgNPs were detected in the liver sections of the tested rats. However, the in vitro system using rat liver microsomes demonstrated a strong inhibition of CYP2C (IC(50)?= 28 μg/mL) and CYP2D (IC(50)?= 23 μg/mL) activities, but not of CYP1A, CYP2E1 and CYP3A activities (IC(50) > 100 μg/mL) at concentrations up to 100 μg/mL of AgNPs. The inhibitory effect of AgNPs on these CYPs indicates the possibility of the AgNP-drug interaction when co-administered with some medicines and this may cause adverse effects to patients. 相似文献
17.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(9):854-862
Silver nanoparticles (AgNPs) are increasingly used in various products and consequentially the potential adverse effects associated with exposure to them are of concern. This study investigated the effects of AgNPs on the hepatic drug-metabolizing enzymes of the cytochrome P450 (CYP) families 1, 2 and 3, using both in vitro and in vivo biological assays. AgNPs were orally administered to Sprague-Dawley rats at various concentrations (0–1000?mg/kg body weight/day) for 2 weeks. No effect was found on the plasma levels of ALT, AST and ALP in all treated rat groups, and no significant change in the activities of CYP1A, CYP2C, CYP2D, CYP2E1 and CYP3A was observed for all tested AgNP doses. The results correlated with the observation that no AgNPs were detected in the liver sections of the tested rats. However, the in vitro system using rat liver microsomes demonstrated a strong inhibition of CYP2C (IC50?=?28 µg/mL) and CYP2D (IC50?=?23 µg/mL) activities, but not of CYP1A, CYP2E1 and CYP3A activities (IC50 > 100 µg/mL) at concentrations up to 100 µg/mL of AgNPs. The inhibitory effect of AgNPs on these CYPs indicates the possibility of the AgNP-drug interaction when co-administered with some medicines and this may cause adverse effects to patients. 相似文献
18.
van Schaik RH 《Therapeutic drug monitoring》2004,26(2):236-240
In the treatment of cancer, a narrow therapeutic window generally exists between toxicity and suboptimal therapy. In addition, interindividual variation in drug metabolism seriously complicates therapy. Genetic polymorphisms in phase 1 and phase 2 enzymes are present in the population and may explain part of the observed interindividual variation in drug pharmacokinetics. For the cytochrome P450 superfamily, information on variant alleles encoding enzymes with decreased activity is rapidly on the increase. The potential of applying pharmacogenetic screening before therapy in the treatment of cancer seems to be greatest for CYP2B6 (cyclophosphamide treatment), CYP2C8 (paclitaxel therapy), and CYP3A5; however, the drugs of interest still need to be identified for this latter enzyme. 相似文献
19.
《Drug metabolism reviews》2012,44(2):162-177
AbstractThe oxidation of carbon–carbon triple bonds by cytochrome P450 produces ketene metabolites that are hydrolyzed to acetic acid derivatives or are trapped by nucleophiles. In the special case of 17α-ethynyl sterols, D-ring expansion and de-ethynylation have been observed as competing pathways. The oxidation of acetylenic groups is also associated with mechanism-based inactivation of cytochrome P450 enzymes. One mechanism for this inactivation is reaction of the ketene metabolite with cytochrome P450 residues essential for substrate binding or catalysis. However, in the case of monosubstituted acetylenes, inactivation can also occur by addition of the oxidized acetylenic function to a nitrogen of the heme prosthetic group. This addition reaction is not mediated by the ketene metabolite, but rather occurs during oxygen transfer to the triple bond. In some instances, a detectable intermediate is formed that is most consistent with a ketocarbene–iron heme complex. This complex can progress to the N-alkylated heme or revert back to the unmodified enzyme. The ketocarbene complex may intervene in the formation of all the N-alkyl heme adducts, but is normally too unstable to be detected. 相似文献
20.
CYP450氧化还原酶的遗传多态对药物代谢的影响 总被引:3,自引:1,他引:2
CYP450氧化还原酶(cytochrome P450 oxidoreductase,POR)是所有肝微粒体的细胞色素P450氧化酶(cytochrome P450 monooxygenases,CYP)的唯一电子供体,其中一些CYP是I相药物代谢酶,负责临床上超过80%药物的氧化代谢。另外,POR直接介导了一些抗肿瘤前体药物的代谢。因此,POR的遗传多态引起其活性的改变,对临床药物代谢具有非常重要的临床意义。该文总结了近年来POR的遗传多态影响药物代谢的最新研究进展。 相似文献