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111.
Metabolism of (‐)‐cis‐ and (‐)‐trans‐rose oxide by cytochrome P450 enzymes in human liver microsomes
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Hiroshi Nakahashi Yuuki Yamamura Atsushi Usami Pramoch Rangsunvigit Pomthong Malakul Mitsuo Miyazawa 《Biopharmaceutics & drug disposition》2015,36(9):565-574
The in vitro metabolism of (‐)‐cis‐ and (‐)‐trans‐rose oxide was investigated using human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes for the first time. Both isomers of rose oxide were incubated with human liver microsomes, and the formation of the respective 9‐oxidized metabolite were determined using gas chromatography‐mass spectrometry (GC‐MS). Of 11 different recombinant human P450 enzymes used, CYP2B6 and CYP2C19 were the primary enzymes catalysing the metabolism of (‐)‐cis‐ and (‐)‐trans‐rose oxide. CYP1A2 also efficiently oxidized (‐)‐cis‐rose oxide at the 9‐position but not (‐)‐trans‐rose oxide. α‐Naphthoflavone (a selective CYP1A2 inhibitor), thioTEPA (a CYP2B6 inhibitor) and anti‐CYP2B6 antibody inhibited (‐)‐cis‐rose oxide 9‐hydroxylation catalysed by human liver microsomes. On the other hand, the metabolism of (‐)‐trans‐rose oxide was suppressed by thioTEPA and anti‐CYP2B6 at a significant level in human liver microsomes. However, omeprazole (a CYP2C19 inhibitor) had no significant effects on the metabolism of both isomers of rose oxide. Using microsomal preparations from nine different human liver samples, (‐)‐9‐hydroxy‐cis‐ and (‐)‐9‐hydroxy‐trans‐rose oxide formations correlated with (S)‐mephenytoin N‐demethylase activity (CYP2B6 marker activity). These results suggest that CYP2B6 plays important roles in the metabolism of (‐)‐cis‐ and (‐)‐trans‐rose oxide in human liver microsomes. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
112.
Yibai Li Kate A Jackson Barry Slon Janet R Hardy Michael Franco Leeroy William Peter Poon Janet K Coller Mark R Hutchinson David C Currow Andrew A Somogyi 《British journal of clinical pharmacology》2015,80(2):276-284
Aims
Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients.Methods
CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k) and norketamine (Css,nk) were determined using HPLC.Results
The median plasma clearance of ketamine after 100 mg 24 h–1 dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h–1) and CYP2B6*1/*6 (40.6 l h–1) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h–1, P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h-1) than those who did not (52.6 l h-1, P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k, respectively. Similar results were observed after higher doses.Conclusions
The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects. 相似文献113.
This article reviews in vitro metabolic activities [including Michaelis constants (Km), maximal velocities (Vmax) and Vmax/Km] and drug–steroid interactions [such as induction and cooperativity (activation)] of cytochromes P450 (P450 or CYP) in human tissues, including liver and adrenal gland, for 14 kinds of endogenous steroid compounds, including allopregnanolone, cholesterol, cortisol, cortisone, dehydroepiandrosterone, estradiol, estrone, pregnenolone, progesterone, testosterone and bile acids (cholic acid). First, we considered the drug-metabolizing P450s. 6β-Hydroxylation of many steroids, including cortisol, cortisone, progesterone and testosterone, was catalyzed primarily by CYP3A4. CYP1A2 and CYP3A4, respectively, are likely the major hepatic enzymes responsible for 2-/4-hydroxylation and 16α-hydroxylation of estradiol and estrone, steroids that can contribute to breast cancer risk. In contrast, CYP1A1 and CYP1B1 predominantly metabolized estrone and estradiol to 2- and 4-catechol estrogens, which are endogenous ultimate carcinogens if formed in the breast. Some metabolic activities of CYP3A4, including dehydroepiandrosterone 7β-/16α-hydroxylation, estrone 2-hydroxylation and testosterone 6β-hydroxylation, were higher than those for polymorphically expressed CYP3A5. Next, we considered typical steroidogenic P450s. CYP17A1, CYP19A1 and CYP27A1 catalyzed steroid synthesis, including hydroxylation at 17α, 19 and 27 positions, respectively. However, it was difficult to predict which hepatic drug-metabolizing P450 or steroidogenic P450 will be mainly responsible for metabolizing each steroid hormone in vivo based on these results. Further research is required on the metabolism of steroid hormones by various P450s and on prediction of their relative contributions to in vivo metabolism. The findings collected here provide fundamental and useful information on the metabolism of steroid compounds. 相似文献
114.
目的 研究异丙酚在人肝微粒体中的代谢。方法 采用高效液相方法测定孵育液中异丙酚的浓度。研究异丙酚的酶促动力学,推导出药物米氏常数(Km)和最大反应速度(Vmax);并计算体外酶对药物的清除率(CLint)。同时观察不同种类的CYP酶特异性抑制剂对异丙酚代谢的影响。结果 异丙酚在人肝微粒体中Km和Vmax分别为777.43μuM和172.413μM?h ?1?mg ?1?protein,Clint为0.22h?1?mg?1?protein。CYP2B6特异性抑制剂氯吡格雷能够显著抑制异丙酚的代谢,而CYP2C9和CYP2C19特异性抑制剂对异丙酚代谢无显著影响CYP2B6抑制剂能够减少异丙酚的代谢。结论 CYP2B6主要参与异丙酚的代谢, CYP2B6酶抑制剂可能会抑制异丙酚的代谢,造成药物药效或毒性的增加。 相似文献
115.
Fatal disseminated herpesvirus hominis type 2 infection in an adult with associated thymic dysplasia 总被引:7,自引:0,他引:7
Disseminated herpesvirus hominis (HVH) type 2 infection, proved by viral isolation, is described in a previously healthy young woman. The clinical course was characterized by rapidly progressive hepatic failure leading to death 1 week after hospitalization. Postmortem examination showed involvement of many organs by HVH, most severe in the liver. The thymus gland showed dysplasia. It is suggested that this thymic alteration was congenital and was associated with a partial deficiency in cellular immunity, which permitted the patient's relatively long survival but ultimately rendered her susceptible to overwhelming viremia. Six adults with disseminated HVH infection, type unspecified but proved by viral isolation, were found in a review of the literature; predisposing factors (steroids, burns, Hodgkin's disease, malnutrition) existed in five patients. The thymus gland was not described, however, in the autopsy reports on any of the five patients who died.It is concluded that in order to initiate early antiviral therapy, HVH should be a diagnostic consideration in adults with hepatitis, particularly if skin or mucosal lesions are present. Furthermore, the central and peripheral lymphoid system of any patient who dies of a disseminated viral infection should be thoroughly examined. 相似文献
116.
Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia 总被引:1,自引:0,他引:1
Pharmacodynamic studies have been used to establish the relationships between the administered dosage and the concentration of drugs and metabolites in the blood or tissues and that between these concentrations and pharmacological effects. Polymorphisms in the genes that encode drug-metabolizing enzymes, drug transporters and drug targets can affect a person's response to therapy and may affect the development of de novo or therapy-related leukaemias. The burgeoning field of pharmacogenomics elucidates inherited differences in drug metabolism and treatment response. Increasingly, pharmacodynamic and pharmacogenomic studies are being used to individualize therapy to enhance efficacy and reduce toxicity. 相似文献
117.
118.
重组腺相关病毒介导的细胞色素P450表氧化酶基因对TNF-α诱导人脐静脉内皮细胞炎症的影响 总被引:1,自引:1,他引:1
目的研究过度表达细胞色素P450表氧化酶基因引起内源性EETs产生增加是否能抑制由TNF—α诱导的内皮炎症。方法以携带三种不同表氧化酶基因的重组腺相关病毒rAAV- CYP2C11、rAAV—CYP2J2和rAAV—CYPF87V转染人脐静脉内皮细胞,然后再以TNF—α干预,来研究它们对内皮VCAM-1的表达及外周血单核细胞PBMC与内皮细胞粘附的影响。结果TNF-α诱导了 HUVEC中VCAM-1蛋白质的表达,rAAV—CYP2C11、rAAV—CYP2J2能明显抑制TNF-α的这一作用。 TNF-α诱导了PBMC与HUVEC的粘附(100±0.0% vs 620.1±65.3%),rAAV-CYP2C11、rAAV- CYP2J2能明显抑制TNF-α的这一作用(分别为120.3±33.4% vs 387.7±27.4%.131.0±28.7% vs 535.0±69.7%)。结论CYP2C11和CYP2J2基因具有显著的保护内皮细胞、对抗炎症介质介导的内皮损伤的作用。 相似文献
119.
120.
Zum Thema
Der genetische Polymorphismus zahlreicher Enzyme bewirkt deutliche interindividuelle und interethnische Unterschiede bei der
Metabolisierung von Pharmaka, die durchaus von klinischer Relevanz sein k?nnen. Neben unerwünschten Arzneimittelwirkungen
kann ein rascherer oder langsamerer Metabolismus zu ernsthaften Erkrankungen bis hin zur Entwicklung von Karzinomen führen.
Die Auswirkungen dieser genetischen Variabilit?t, die sich mittels Genotypisierung darstellen l?sst, werden in diesem Beitrag
am Beispiel eines Isoenzyms des Cytochrom P450-Systems und der N-Acetyltransferase eingehend dargestellt. Auch verschiedene
Erkrankungen k?nnen sich auf die Pharmakokinetik und Pharmakodynamik von Medikamenten auswirken. Besonders bei ?lteren, multimorbiden
Patienten werden diese Interaktionen h?ufig nicht ausreichend berücksichtigt. Die Auswirkungen von Leberfunktionsst?rungen
und Niereninsuffizienz werden daher nachfolgend ausführlicher erl?utert. 相似文献