丝裂霉素C在体外和体内对大鼠肝脏CYP2D1/2,CYP2C11和CYP1A2活性的影响

目的研究丝裂霉素C(MMC)在体外和体内对大鼠肝脏CYP2D1/2,CYP2C11和CYP1A2活性的影响。方法用诱导剂和抑制剂分别在体内和体外调节大鼠肝脏P450同工酶活性，并用HPLC检测3种同工酶各自底物的特定代谢产物，以计算同工酶活性。结果在体外, MMC可以使地塞米松诱导的大鼠肝脏微粒体CYP2D1/2,CYP2C11和CYP1A2活性分别抑制(19±6)%(P<0.05),(85±10)％(P<0.01)和(36±6)%(P<0.05)，并使β-萘黄酮诱导的CYP1A2活性降低(58±6)%(P<0.01)。在体内，以20% LD₅₀的剂量连续3 d或6 d腹腔注射MMC 对大鼠肝脏CYP2D1/2，CYP2C11和CYP1A2活性的影响无统计学差异。结论在体外MMC可以抑制大鼠肝微粒体CYP2D1/2，CYP2C11和CYP1A2的活性，但在体内对这3种细胞色素P450同工酶活性的影响无统计学差异。     

重组肝CYP3A4与CYP3A29细胞微粒体药物代谢动力学比较

目的 比较巴马小型猪CYP3A29和人CYP3 A4稳定表达重组肝癌细胞株微粒体的药物代谢特征,在分子水平为巴马小型猪作为临床前药物代谢实验动物提供科学依据.方法 以CYP3A特异性代谢底物硝苯地平、睾酮及其抑制药酮康唑为探针药物,将探针药物与重组CYP3A4、CYP3A29细胞微粒体在优化的微粒体浓度、药物浓度、孵育时间等条件下进行体外孵育,高效液相色谱法检测其药物代谢(抑制)动力学参数,并将二者进行比较分析.结果 巴马小型猪CYP3A29与CYP3A4在硝苯地平和睾酮代谢差异无统计学意义(P＞0.05).酮康唑的抑制活性为:当代谢底物为硝苯地平时,酮康唑对CYP3A29和CYP3A4的半数抑制浓度分别为0.090,0.132 μmol·L-1(P＜0.05);当代谢底物为睾酮时,酮康唑对CYP3A29和CYP3A4的半数抑制浓度分别为0.056,0.032 μmol·L-1(P＜0.05).结论 重组CYP3A29与CYP3 A4细胞微粒体对硝苯地平和睾酮活性差异不显著;酮康唑对重组CYP3A29与CYP3A4细胞微粒体硝苯地平和睾酮代谢活性有差异.     

酮康唑对大鼠肝脏CYP450酶系的影响*

目的:观察酮康唑对大鼠肝细胞色素P450及其主要亚型的影响。方法:Sprague-Dawley大鼠用140,280,420μmol.kg-1.d-1酮康唑连续灌胃7 d,测定肝脏微粒体中总CYP450含量和CYP1A1,1A2,1B1,2B1/2,2E1和3A亚型活性。结果:不同剂量酮康唑给药后大鼠肝脏脏器系数、CYP1A1和1B1亚型活性明显增高(P<0.05,P<0.01);总CYP450含量和CYP3A活性显著降低(P<0.01);低剂量的酮康唑抑制CYP1A2和CYP2B1/2亚型的活性,高剂量却出现了诱导作用(P<0.05,P<0.01)。各剂量组对CYP2E1均无明显影响。结论:酮康唑对大鼠肝脏CYP450及主要药物代谢亚型CYP1A1,1A2,1B1,2B1/2和3A有影响,临床长期用药或与经肝脏CYP450代谢的药物联合应用时要注意监测血药浓度和肝脏功能,防止药物代谢减缓出现蓄积中毒或药物代谢加快而降低药效。     

羟基喜树碱的代谢与CYP450的相关性研究

目的：研究羟基喜树碱（HCPT）在体外小鼠肝微粒体中对 CYP450活性的影响,为临床合理联合用药提供参考。方法：在小鼠体外肝微粒体中分别加入六种亚型酶的探针药物对乙酰氨基酚、非那西丁、双氯芬酸钠、睾酮、酒石酸美托洛尔、奥美拉唑和羟基喜树碱溶液,在优化的孵育体系下温孵。用 HPLC 法测定各空白对照组和羟基喜树碱溶液中各探针药物代谢产物的浓度并比较代谢率的差异,以评价羟基喜树碱对各亚型酶活性的影响。结果：在代谢反应过程中,在50~200μmol·L-1内,羟基喜树碱的浓度与孵育体系中 CYP3A4的特异性底物睾酮、CYP2E1的特异性底物对乙酰氨基酚的剩余药量呈正比例关系,且具显著性差异（P＜0.05）,与其他四种探针药物的剩余药量无明显的浓度依存关系（P＞0.05）。结论：HCPT 在肝微粒体的代谢反应过程中受代谢酶 CYP3A4和 CYP2E1的作用,竞争性地抑制了睾酮和对乙酰氨基酚在肝微粒体中的代谢。     

建立用大鼠肝微粒体快速考察药物体外CYP3A1活性抑制的方法

目的研究酮康唑对大鼠肝微粒体细胞色素P450同工酶3A1（CYP3A1）活性的作用,建立一种用大鼠肝微粒体快速考察药物体外CYP3A1活性抑制的方法。方法采集大鼠肝微粒体,随机分为对照组和药物处理组。酮康唑药物处理组分别加入不同浓度的酮康唑,对照组只加入培养液,混匀后放入37℃培养箱中孵育15 min,然后加入CYP 3A1底物睾酮,继续孵育10 min,最后加入内标物氢化可的松。用HPLC法测定睾酮经大鼠肝微粒体温孵后生成6-β羟基睾酮的量,代表CYP3A1的活性。结果各个处理组与对照组的比较差异均有显著性差异（P〈0.05）;提示在一定浓度范围内,大鼠同工酶CYP3A1的相对活性百分比随着酮康唑浓度的增加而逐渐减低,各处理组与对照组比较差异均有显著性意义（P〈0.5）。半数抑制浓度（IC50）值为3.25μg/ml。结论酮康唑对大鼠肝微粒体细胞色素P450同工酶3A1的活性有强抑制作用,建立的通过大鼠肝微粒体快速考察药物体外CYP3A1探针抑制的方法重复性和稳定性均良好,为评价新药对大鼠肝微粒体CYP3A1的活性的体外作用提供可靠的检测手段。     

建立用大鼠肝微粒体快速考察药物体外CYP3A1活性抑制的方法

目的 研究酮康唑对大鼠肝微粒体细胞色素P450同工酶3A1( CYP3A1)活性的作用,建立一种用大鼠肝微粒体快速考察药物体外CYP3A1活性抑制的方法.方法 采集大鼠肝微粒体,随机分为对照组和药物处理组.酮康唑药物处理组分别加入不同浓度的酮康唑,对照组只加入培养液,混匀后放入37℃培养箱中孵育15 min,然后加入CYP 3A1底物睾酮,继续孵育10 min,最后加入内标物氢化可的松.用HPLC法测定睾酮经大鼠肝微粒体温孵后生成6-β羟基睾酮的量,代表CYP3A1的活性.结果 各个处理组与对照组的比较差异均有显著性差异(P＜0.05);提示在一定浓度范围内,大鼠同工酶CYP3A1的相对活性百分比随着酮康唑浓度的增加而逐渐减低,各处理组与对照组比较差异均有显著性意义(P＜0.5).半数抑制浓度( IC50)值为3.25 μg/ml.结论 酮康唑对大鼠肝微粒体细胞色素P450同工酶3A1的活性有强抑制作用,建立的通过大鼠肝微粒体快速考察药物体外CYP3A1探针抑制的方法重复性和稳定性均良好,为评价新药对大鼠肝微粒体CYP3A1的活性的体外作用提供可靠的检测手段.     

淫羊藿总黄酮对大鼠肝微粒体CYP1A2、CYP3A4和CYP2E1活性的影响

评估淫羊藿总黄酮对大鼠肝细胞色素P450及其主要亚型活性的潜在影响。淫羊藿总黄酮以300mg／kg／d的剂量对SD大鼠进行连续灌胃处理15天，测定肝微粒体中cYP450含量与CYP1A2、CYP3A4和CYP2E1亚型活性，观察淫羊藿总黄酮的效应。CYP1A2的活性用荧光比色法进行测定，CYP3A4和CYP2E1的活性用紫外可见分光光度法测定。淫羊藿总黄酮处理后的大鼠肝脏CYP450含量及CYP1A2、CYP3A4和CYP2E1亚型活性均明显增高，其中CYP1A2和CYP2E1活性升高显著（P〈0．01）。淫羊藿总黄酮对大鼠肝脏CYP450及主要亚型CYP1A2、CYP3A4和CYP2E1活性均有诱导效应。     

血塞通注射液对鼠肝CYP3A体外抑制作用研究

目的：研究血塞通注射液对大鼠肝微粒体CYP3A酶活性的体外抑制作用。方法：在大鼠肝微粒体体外孵育体系中加入CYP3A酶的底物睾酮和不同体积的血塞通注射液,用高效液相色谱法测定睾酮的羟化代谢产物6β-羟基睾酮的生成量反映CYP3A酶的活性。酮康唑为阳性对照药。结果：在大鼠肝微粒体体外孵育体系中,血塞通注射液对CYP3A酶的IC50和Ki值分别为血塞通注射液原液的0．87％和0．43％。结论：血塞通注射液在体外对大鼠肝微粒体CYP3A酶活性有抑制作用,符合混合型抑制模型。     

振源胶囊对细胞色素P_(450)酶CYP1A2、CYP3A4、CYP2E1的影响

目的:研究振源胶囊对细胞色素P450酶CYP1A2、CYP3A4、CYP2E1的影响。方法:用Cocktail探针药物法,将Wistar大鼠随机分组,灌胃给予振源胶囊溶液,以生理盐水组为空白对照,诱导10d,于股动脉插管,注射给予3种探针药物咖啡因、氨苯砜、氯唑沙宗,通过高效液相色谱法检测各探针药物的代谢率来评价各组CYP1A2、CYP3A4、CYP2E1亚型酶的活性;药动学计算采用DAS2.0软件完成。结果:给予振源胶囊的大鼠,咖啡因代谢加快,半衰期缩短;氨苯砜代谢减慢,半衰期延长;氯唑沙宗半衰期与空白对照组比较无显著差异(P>0.05)。结论:振源胶囊对大鼠CYP1A2有诱导作用,对CYP3A4有抑制作用,对CYP2E1的作用不明显。     

黄芪颗粒和黄芪注射液对CYP1A2、CYP2D、CYP2C亚酶活性影响的实验研究

目的通过体内和体外实验研究黄芪颗粒和黄芪注射液对CYP1A2、CYP2D、CYP2C亚酶的活性影响。方法建立体外"cocktail"反应体系,利用LC/MS/MS法测定酶代谢产物,计算黄芪颗粒和黄芪注射液对CYP1A2、CYP2D6、CYP2C9和CYP2C19亚酶活性的影响;大鼠随机分为对照组和实验组,不同浓度黄芪颗粒和黄芪注射液连续灌胃10 d,制备肝微粒体并进行"cocktail"反应,评价两种药物体内对大鼠CYP1A2、CYP2D1、CYP2C6和CYP2C11亚酶活性影响。结果在体外"cocktail"实验中,黄芪颗粒和黄芪注射液明显地抑制了CYP2D6、CYP2C19和CYP1A2亚酶活性,而二者对于CYP2C9亚酶活性无影响。在大鼠灌胃给药实验中,黄芪颗粒在剂量32、160和800 mg.kg-1.d-1提高CYP1A2亚酶活性2.13、3.23和2.20倍,黄芪注射液在剂量0.16、0.8、4 g.kg-1.d-1提高CYP1A2亚酶活性1.65、2.26和2.89倍,而二者均未诱导CYP2D1、CYP2C6和CYP2C11亚酶活性增加。结论黄芪颗粒和黄芪注射液对CYP2D6、CYP2C19活性有抑制作用,对大鼠CYP1A2活性有诱导作用。     

Molecular modelling of CYP1 family enzymes CYP1A1, CYP1A2, CYP1A6 and CYP1B1 based on sequence homology with CYP102

Molecular modelling of a number of CYP1 family enzymes from rat, plaice and human is described based on amino acid sequence homology with the haemoprotein domain of CYP102, a unique bacterial P450 of known structure. The interaction of various substrates and inhibitors within the putative active sites of rat CYP1A1, human CYP1A2, a fish CYP1 enzyme CYP1A6 (from plaice) and human CYP1B1, is shown to be consistent with P450-mediated oxidation in each example or, in the case of inhibitors, mechanism of inhibition. It is reported that relatively small changes between the enzymes' active site regions assist in the rationalization of CYP1 enzyme preferences for particular substrate types, and a template of superimposed CYP1A2 substrates is shown to fit the putative active site of the human CYP1A2 enzyme.     

Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro

Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC₅₀ value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC₅₀ values greater than 250 μg/ml. Hence there appears to be little likelihood of drug–herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.     

Effects of notoginsenoside R1 on CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 activities in rats by cocktail probe drugs

Context: Notoginsenoside R1 (NGR1) is the main component with cardiovascular activity in Panax notoginseng (Burk.) F. H. Chen, an herbal medicine that is widely used to enhance blood circulation and dissipate blood stasis.

Objective: The objective of this study is to investigate NGR1's effects on CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 activities in rats in vivo through the use of the Cytochrome P450 (CYP450) probe drugs.

Materials and methods: After pretreatment with NGR1 or physiological saline, the rats were administered intraperitoneally with a mixture solution of cocktail probe drugs containing caffeine (10?mg/kg), tolbutamide (15?mg/kg), metoprolol (20?mg/kg), and dapsone (10?mg/kg). The bloods were then collected at a set of time-points for the ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis.

Results: NGR1 was shown to exhibit an inhibitory effect on CYP1A2 by increased caffeine C_max (43.13%, p?<?0.01) and AUC_0???∞ (40.57%, p?<?0.01), and decreased CL/F (62.16%, p?<?0.01) in the NGR1-treated group compared with those of the control group, but no significant changes in pharmacokinetic parameters of tolbutamide, metoprolol, and dapsone were observed between the two groups, indicating that NGR1 had no effects on rat CYP2C11, CYP2D1, and CYP3A1/2.

Discussion and conclusion: When NGR1 is co-administered with drugs that are metabolized by CYP1A2, the pertinent potential herb–drug interactions should be monitored.     

Pharmacogenomics of CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and MDR1 in Vietnam

Aim  The aim of this study was to obtain pharmacogenetic data in a Vietnamese population on genes coding for proteins involved in the elimination of drugs currently used for the treatment of malaria and human immunodeficiency virus/acquired immunodeficiency syndrome. Method  The main polymorphisms on the cytochrome P450 (CYP) genes, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, and the multi-drug resistance 1 gene (MDR1) were genotyped in 78 healthy Vietnamese subjects. Pharmacokinetic metrics were available for CYP2A6 (coumarin), CYP2C19 (mephenytoin), CYP2D6 (metoprolol) and CYP3As (midazolam), allowing correlations with the determined genotype. Results  In the CYP2 family, we detected alleles CYP2A6*4 (12%) and *5 (15%); CYP2B6*4 (8%), *6 (27%); CYP2C19*2 (31%) and *3 (6%); CYP2D6*4, *5, *10 (1, 8 and 44%, respectively). In the CYP3A family, CYP3A4*1B was detected at a low frequency (2%), whereas CYP3A5 *3 was detected at a frequency of 67%. The MDR1 3435T allele was present with a prevalence of 40%. Allele proportions in our cohort were compared with those reported for other Asian populations. CYP2C19 genotypes were associated to the S-4′-OH-mephenytoin/S-mephenytoin ratio quantified in plasma 4 h after intake of 100 mg mephenytoin. While CYP2D6 genotypes were partially reflected by the α-OH-metroprolol/metoprolol ratio in plasma 4 h after dosing, no correlation existed between midazolam plasma concentrations 4 h post-dose and CYP3A genotypes. Conclusions  The Vietnamese subjects of our study cohort presented allele prevalences in drug-metabolising enzymes that were generally comparable with those reported in other Asian populations. Deviations were found for CYP2A6*4 compared to a Chinese population (12 vs. 5%, respectively; P = 0.023), CYP2A6*5 compared with a Korean population (15 vs. <1%, respectively; P < 0.0001), a Malaysian population (1%; P < 0.0001) and a Chinese population (1%; P < 0.0001); CYP2B6*6 compared with a Korean population (27 vs. 12%; P = 0.002) and a Japanese population (16%; P = 0.021). Pharmacokinetic metrics versus genotype analysis reinforces the view that the predictive value of certain globally common variants (e.g. CYP2D6 single nucleotide polymorphisms) should be evaluated in a population-specific manner.     

Inhibition of heme oxygenase-1 partially reverses the arsenite-mediated decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 catalytic activity in isolated rat hepatocytes

Heme oxygenase (HO-1), the rate-limiting enzyme in the physiological breakdown of heme, is ubiquitous, and its expression can be increased by arsenite [As(III)], and similar other stimuli that induce cellular oxidative stress. Interestingly, it has been shown that the As(III)-induced HO-1 is inversely correlated with a decrease in cytochromes P450 (P450s) activity; however, the direct role for HO-1 in the inhibition of P450 enzymes remains unknown. Our results showed that As(III) at a concentration of 5 μM decreased the constitutive and inducible expression of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 at the mRNA, protein, and catalytic activity levels. Moreover, As(III) decreased the nuclear accumulation of aryl hydrocarbon receptor (AhR) and pregnane X receptor without increasing their degradation. As(III) also increased the binding of cytosolic AhR to heat shock protein 90 and hepatitis B virus X-associated protein 2. In the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin as an inducer for CYP1A and rifampin as an inducer for CYP3A, As(III) decreased the enzymatic activity of the four P450s more than it decreased their mRNA or protein expression levels. It is noteworthy that treatment with the competitive HO-1 inhibitor, tin-mesoporphyrin, or supplementing external heme partially reversed the As(III)-mediated decrease in activities of the four P450s. In conclusion, the current study provides the first evidence that As(III) decreases CYP1A1, CYP1A2, CYP3A23, and CYP3A2 expression in freshly isolated rat primary hepatocytes. Furthermore, inhibiting the As(III)-mediated induction of HO-1 partially restores the enzymatic activity of these P450s that was initially decreased by As(III), confirming the direct role of HO-1 in the inhibition of P450s.     

Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population

Objective The frequency of functionally important mutations and alleles of genes coding for xenobiotic metabolizing enzymes shows a wide ethnic variation. However, little is known of the frequency distribution of the major allelic variants in the Russian population.Methods Using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) genotyping assays and the real-time PCR with fluorescent probes, the frequencies of functionally important variants of the cytochromes P₄₅₀ (CYP) 2C9, 2C19, 2D6, 1A1 as well as arylamine N-acetyltransferase 2 (NAT2) and P-glycoprotein (MDR1) were determined in a sample of 290 Russian volunteers derived from Voronezh area.Results CYP2C9*2 and *3 alleles were found with allelic frequencies of 10.5% and 6.7%, respectively. The novel intron-2 T>C mutation at exon 2 +73 bp occurred in 24.8% of alleles. CYP2C19*2 and *3 alleles occurred in 11.4% and 0.3%, respectively. Six persons (2.1%) carried two of these CYP2C19 alleles responsible for poor metabolizing activity. Of all subjects, 5.9% were CYP2D6 poor metabolizers, whereas 3.4% were addressed to ultra-rapid metabolizers (CYP2D6*1×2/*1). The CYP1A1*2A allele was found in 4.7%, *2B in 5.0%, *4 in 2.6%, and the 5-mutations –3219C>T, –3229G>A, and the novel –4335G>A in 6.0%, 2.9% and 26.0% of alleles, respectively. Genotyping of eight different single nucleotide polymorphisms in the NAT2 gene provided in 58.0% a genotype associated with slow acetylation. The MDR1 triple variants G2677T and G2677A in exon 21 had an allelic frequency of 41.9% and 3.3%, respectively, and the variant C3435T in exon 26 one of 54.3%. Frequencies of functionally important haplotypes were calculated.Conclusion The overview of allele distribution of important xenobiotic-metabolizing enzymes among a Russian population shows similarity to other Caucasians. The data will be useful for clinical pharmacokinetic investigations and for drug dosage recommendations in the Russian population.     

Oxidation of the flavonoids galangin and kaempferide by human liver microsomes and CYP1A1, CYP1A2, and CYP2C9.

There is very limited information on cytochrome P450 (P450)-mediated oxidative metabolism of dietary flavonoids in humans. In this study, we used human liver microsomes and recombinant P450 isoforms to examine the metabolism of two flavonols, galangin and kaempferide, and one flavone, chrysin. Both galangin and kaempferide, but not chrysin, were oxidized by human liver microsomes to kaempferol, with K(m) values of 9.5 and 17.8 microM, respectively. These oxidations were catalyzed mainly by CYP1A2 but also by CYP2C9. Consistent with these observations, the human liver microsomal metabolism of galangin and kaempferide were inhibited by the P450 inhibitors furafylline and sulfaphenazole. In addition, CYP1A1, although less efficient, was also able to oxidize the two flavonols. Thus, dietary flavonols are likely to undergo oxidative metabolism mainly in the liver but also extrahepatically.     

Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide

PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4-hydroxycyclophosphamide. EXPERIMENTAL DESIGN: A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4-hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling. RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-hydroxycyclophosphamide could be demonstrated. CONCLUSION: This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity.     

甘遂与甘草合用对大鼠肝药酶CYP1A2、CYP2C19和CYP2E1的影响

<正>"十八反"则告诫人们,甘遂(Euphorbia kansui,EK)与甘草(Glycyrrhiza uralensis,GU)相对立不宜伍用。但有学者认为,反药同用能相反相成,产生较强的功效。故一直以来,甘遂与甘草组合在临床上仍有广泛的应用~([1-3])。近年来,中药用药的安全性问题越来越受到重视,阐明"反"的机制,已成为中医药理论自身发展的必然要求。药物相互作用中最常见的原因是CYP450的诱导和抑制~([4-5])。中药虽然成分复杂,但效应成分多数仍要通过