The in vitro inhibition of human CYP1A2, CYP2D6 and CYP3A4 by tetrahydropalmatine, neferine and berberine

The purpose of this study was to investigate the in vitro inhibition potential of the three purified herbal constituents tetrahydropalmatine (Tet), neferine (Nef) and berberine (Ber) towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. In vitro incubations were performed with phenacetin, dextromethorphan and testosterone, respectively, as CYP substrates and their metabolites were determined by validated HPLC methods. Positive control inhibitors were run for each CYP in all incubation series. Inhibition was expressed by IC₅₀ values. All herbal constituents demonstrated some, but variable, inhibition potencies towards the investigated CYP enzymes. CYP2D6 was the most sensitive for inhibition and then mainly by Tet and Ber with IC₅₀ values of 3.04 ± 0.26 µm and 7.40 ± 0.36 µm , respectively. CYP3A4 and especially CYP1A2 were inhibited to a much smaller extent by all constituents. Neferine showed the lowest overall interaction potential towards the CYP enzymes investigated. The CYP inhibition potential for the purified constituents could be related to their chemical structures. No clinical significant metabolic interaction seems likely to occur between the CYP enzymes and herbal constituents tested, with a possible exception for the CYP2D6 inhibition by Tet and Ber. Copyright © 2011 John Wiley & Sons, Ltd.     

Investigation of CYP3A4 and CYP2D6 Interactions of Withania somnifera and Centella asiatica in Human Liver Microsomes

Withania somnifera is commonly used as a rejuvenator, whereas Centella asiatica is well known for its anxiolytic and nootropic effects. The present study aims at investigating the effect of crude extracts and principal phytoconstituents of both the medicinal plants with CYP3A4 and CYP2D6 enzyme activity in human liver microsomes (HLM). Phytoconstituents were quantified in the crude extracts of both the medicinal plants using reverse phase HPLC. Crude extracts and phytoconstituents of W. somnifera showed no significant interaction with both CYP3A4 and CYP2D6 enzymes in HLM. Of the crude extracts of C. asiatica screened in vitro, methanolic extract showed potent noncompetitive inhibition of only CYP3A4 enzyme (Ki—64.36 ± 1.82 µg/mL), whereas ethanol solution extract showed potent noncompetitive inhibition of only CYP2D6 enzyme (Ki—36.3 ± 0.44 µg/mL). The flavonoids, quercetin, and kaempferol showed potent (IC₅₀ values less than 100 μM) inhibition of CYP3A4 activity, whereas quercetin alone showed potent inhibition of CYP2D6 activity in HLM. Because methanolic extract of C. asiatica showed a relatively high percentage content of quercetin and kaempferol than ethanol solution extract, the inhibitory effect of methanolic extract on CYP3A4 enzyme activity could be attributed to the flavonoids. Thus, co‐administration of the alcoholic extracts of C. asiatica with drugs that are substrates of CYP3A4 and CYP2D6 enzymes may lead to undesirable herb‐drug interactions in humans. Copyright © 2015 John Wiley & Sons, Ltd.     

Cytochrome P450 Inhibition Assay for Standardized Extract of Terminalia chebula Retz.

The hydroalcoholic extract of fruit pulp of Terminalia chebula Retz. was standardized and evaluated for its safety through cytochrome P450 (CYP 450) inhibition assay. Standardization was performed through high performance thin layer chromatography (HPTLC) using gallic acid (GA) standard. Cytochrome P450‐CO complex microplate assay was performed using rat liver microsomes. The effect of standardized extract, its fraction and bioactive marker compound were comparatively evaluated for its effect on CYP P450 enzymes. The extract of fruit pulp was used for HPTLC, where the R_f value of the marker was found to be 0.43. The calibration plot was linear in the range of 2–14 µg of GA and correlation co‐efficient of 0.99965. The mean quantity of GA was found to be 2.5% w/w. The CYP P450 concentration of the rat liver microsome sample used in the study was found to be 0.417 nmol/mg protein. The in vitro effect of various concentrations of extracts and fractions showed a linear concentration‐dependent inhibition of cytochrome P450 up to 60 µL. The study showed more inhibition of fraction when compared to the extract and GA. Still, the inhibition showed by fraction is less when compared with standard Ketoconazole. Thus, this study indicated the in vitro cytochrome P450 inhibition potential of T. Chebula.     

Drug interaction potential of the seed extract of Urtica urens L. (dwarf Nettle)

Dwarf nettle (Urtica urens) seed extract was examined in vivo in the rat for its potential to modulate drug metabolizing enzymes including aminopyrine N‐demethylase (APND; CYP2C6), aniline 4‐hydroxylase (A4H; CYP2E1), nitrosodimethylamine N‐demethylase (NDMA‐ND; CYP2E1) erythromycin N‐demethylase (ERND; CYP3A1) CYP2D1/2 and glutathione S‐transferase (GST). RT‐PCR data and western blotting studies clearly demonstrated that CYP2C6 and CYP2E1 mRNA levels were substantially increased after Urtica treatment, while the level of CYP3A1 mRNA decreased and that of CYP2D1/2 remained unchanged. Urtica treatment significantly induced GST activity in the liver, lung and kidney (66‐, 46‐ and 31‐fold, respectively) while decreasing that of APND (35‐, 61‐ and 94‐fold) and NDMA‐ND (23, 28 and 54‐fold). ERND activity in liver was reduced 45‐fold, but increased in the lung and kidney (78‐ and 144‐fold) after Urtica treatment. These results indicate that Urtica seed extract may have the potential to inhibit and/or induce the metabolism of certain co‐administered drugs. Copyright © 2009 John Wiley & Sons, Ltd.     

Effects of Panax notoginseng saponins on the activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in rats in vivo

The aim of this study was to assess the influence of the Panax notoginseng saponins (PNS) on the activities of the drug‐metabolizing enzymes cytochrome P450 (CYP450) 1A2, 2 C9, 2D6 and 3A4 in rats. The activities of CYP1A2, 2 C9, 2D6 and 3A4 were measured using specific probe drugs. After pretreatment for 1 week with PNS or physiological saline (control group), probe drugs caffeine (10 mg/kg; CYP1A2 activity), tolbutamide (15 mg/kg; CYP2C9 activity), metoprolol (20 mg/kg; CYP2D6 activity) and dapsone (10 mg/kg; CYP3A4 activity) were administered to rats by intraperitoneal injection. The blood was then collected at different times for ultra performance liquid chromatography/tandem mass spectrometry (UPLC‐MS/MS) analysis. The data showed that PNS exhibited an induction effect on CYP1A2 by decreasing caffeine C_max (36.3%, p < 0.01) and AUC_0‐∞ (22.77%, p < 0.05) and increasing CL/F (27.03%, p < 0.05) compared with those of the control group. Western blot analysis was used to detect the effect of PNS on the protein level of CYP1A2, and the results showed that PNS could upregulate the protein expression of CYP1A2. However, no significant changes in CYP2C9, 2D6 or 3A4 activities were observed. In conclusion, the results indicate that PNS could induce CYP1A2, which may affect the disposition of medicines primarily dependent on the CYP1A2 pathway. Our work may be the basis of related herb–drug interactions in the clinic. Copyright © 2011 John Wiley & Sons, Ltd.     

In vitro Inhibition of Human CYP1A2, CYP2D6, and CYP3A4 by Six Herbs Commonly Used in Pregnancy

Black elderberry, cranberry, fennel, ginger, horsetail, and raspberry leaf, herbs frequently used in pregnancy, were investigated for their in vitro CYP1A2, 2D6, and 3A4 inhibitory potential. Aqueous or ethanolic extracts were made from commercially available herbal products, and incubations were performed with recombinant cDNA‐expressed human CYP enzymes in the presence of positive inhibitory controls. Metabolite formation was determined by validated LCMS/MS or HPLC methodologies. IC₅₀ inhibition constants were estimated from CYP activity inhibition plots using non‐linear regression. The most potent inhibition was shown for fennel towards CYP2D6 and 3A4 with respective IC₅₀ constants of 23 ± 2 and 40 ± 4 µg/ml, horsetail towards CYP1A2 with an IC₅₀ constant of 27 ± 1 µg/ml, and raspberry leaf towards CYP1A2, 2D6, and 3A4 with IC₅₀ constants of 44 ± 2, 47 ± 8, and 81 ± 11 µg/ml, respectively. Based on the recommended dosing of the different commercial herbal products, clinically relevant systemic CYP inhibitions could be possible for fennel, horsetail, and raspberry leaf. In addition, fennel and raspberry leaf might cause a clinically relevant inhibition of intestinal CYP3A4. The in vivo inhibitory potential of these herbs towards specific CYP enzymes should be further investigated. Copyright © 2013 John Wiley & Sons, Ltd.     

Aloe vera juice: IC₅₀ and dual mechanistic inhibition of CYP3A4 and CYP2D6

The aim of this study was to evaluate the inhibitory potency (IC₅₀ values) of ethanol extracts of two commercially available aloe vera juice (AVJ) products, on CYP3A4 and CYP2D6 activities in vitro and to determine if such inhibitions could be mechanism‐based. Recombinant human CYP3A4 and CYP2D6 enzymes were used and the activities were expressed by the metabolism of testosterone and dextromethorphan with ketoconazole and quinidine as positive inhibitor controls, respectively. The formed metabolites were quantified by validated HPLC techniques. Time‐ and NADPH‐ dependent inhibition assays were performed to evaluate a possible mechanism‐based inhibition. One of the AVJ extracts showed about twice the inhibitory potency towards both CYP enzymes over the other with IC₅₀ values of 8.35 ± 0.72 and 12.5 ± 2.1 mg/mL for CYP3A4 and CYP2D6, respectively. The AVJ was found to exert both CYP mediated and non‐CYP mediated inhibition of both CYP3A4 and CYP2D6. This dual mechanistic inhibition, however, seems to be governed by different mechanisms for CYP3A4 and CYP2D6. Estimated IC₅₀ inhibition values indicate no major interference of AVJ with drug metabolism in man, but the dual mechanistic inhibition of both enzymes might be of clinical significance. Copyright © 2011 John Wiley & Sons, Ltd.     

Inhibition of human cytochrome P450 enzymes 3A4 and 2D6 by β-carboline alkaloids, harmine derivatives

β‐Carboline alkaloids are the main chemical constituents of the plant Peganum harmala, while they also could be formed endogenously and found in coffee, alcoholic beverages and tobacco. Considering the fact that the possibility of herb–drug interactions has recently received great attention worldwide, the aim of the current study was to assess the potential for the metabolism‐based drug–drug interactions arising from five β‐carboline alkaloids (harmine, harmaline, harmalol, harmol and harmane) from P. harmala in vitro. With microsome incubation assays and UPLC/HPLC methods, the inhibitions on human liver CYP3A4 and CYP2D6 enzymes by those β‐carboline alkaloids were studied kinetically. Harmine, harmol and harmane exhibited noncompetitive inhibition on the activity of CYP3A4 with K_i values of 16.76, 5.13 and 1.66 μm , respectively. These β‐carboline alkaloids were also found to be both substrates and inhibitors for CYP2D6. Harmaline, harmine and harmol showed typical competitive inhibition on the activity of CYP2D6 with K_i values of 20.69, 36.48 and 47.11 μm , respectively. The inhibition of the two major CYP enzymes by those β‐carboline alkaloids suggested that changes in the pharmacokinetics of co‐administered drugs were likely to have occurred. Therefore, caution should be exercised for possible drug interactions of medicinal plants containing those β‐carboline alkaloids and CYP substrates. Copyright © 2011 John Wiley & Sons, Ltd.     

Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs

The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were explored in vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism‐based (irreversible) inhibition was assessed by time‐dependent and nicotinamide adenine dinucleotide phosphate‐dependent and reversible inhibition by Lineweaver–Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism‐based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism‐based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhibition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H‐bond and several Pi‐bond connections with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb–drug interactions. Tetrahydropalmatine and Ber should be considered for herb–drug interactions in clinical therapy until relevant clinical studies are available. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of Crude Extract of Eugenia jambolana Lam. on Human Cytochrome P450 Enzymes

The fruit of Eugenia jambolana Lam. is very popular for its anti‐diabetic property. Previous studies on the crude extract of E. jambolana (EJE) have successfully explored the scientific basis for some of its traditional medicinal uses. Considering its wide use and consumption as a seasonal fruit, the present study investigates the ability of E. jambolana to interact with cytochrome P450 enzymes. The standardized EJE was incubated with pooled human liver microsomes to assess the CYP2C9‐, CYP2D6‐, and CYP3A4‐mediated metabolism of diclofenac, dextromethorphan, and testosterone, respectively. The metabolites formed after the enzymatic reactions were quantified by high performance liquid chromatography. EJE showed differential effect on cytochrome P450 activities with an order of inhibitory potential as CYP2C9 > CYP3A4 > CYP2D6 having IC₅₀ of 76.69, 359.02, and 493.05 µg/mL, respectively. The selectivity of EJE for CYP2C9 rather than CYP3A4 and CYP2D6 led to perform the enzyme kinetics to explicate the mechanism underlying the inhibition of CYP2C9‐mediated diclofenac 4′‐hydroxylation. EJE was notably potent in inhibiting the reaction in a non‐competitive manner with K_i of 84.85 ± 5.27 µg/mL. The results revealed the CYP2C9 inhibitory potential of EJE with lower K_i value suggesting that EJE should be examined for its potential pharmacokinetic and pharmacodynamic interactions when concomitantly administered with other drugs. Copyright © 2014 John Wiley & Sons, Ltd.     

Inhibitory and inductive effects of Corydalis saxicola Bunting total alkaloids (CSBTA) on cytochrome P450s in rats

Corydalis saxicola Bunting, a well‐known traditional Chinese medicine in south China, has been widely used for the treatment of various hepatic diseases. Its active ingredients are Corydalis saxicola Bunting total alkaloids (CSBTA), which primarily include dehydrocavidine, palmatine, and berberine. These representative alkaloids could be metabolized by hepatic CYP450s. Hence, it is necessary to investigate the potential influences of CSBTA on CYP450s to explore the possibility of herb–drug interactions. In present study, in vitro inhibition and in vivo induction studies were performed to evaluate the potential effects of CSBTA extract on CYP450s in rats. Inhibition assay illustrated that CSBTA exerted inhibitory effects on CYP1A2 (IC₅₀, 38.08 μg/ml; K_i, 14.3 μg/ml), CYP2D1 (IC₅₀, 20.89 μg/ml; K_i, 9.34 μg/ml), CYP2C6/11 (IC₅₀ for diclofenac and S‐mephenytoin, 56.98 and 31.59 μg/ml; K_i, 39.0 and 23.8 μg/ml), and CYP2B1 (IC₅₀, 48.49 μg/ml; K_i, 36.3 μg/ml) in a noncompetitive manner. Induction study showed CSBTA had obvious inhibitory rather than inductive effects on CYP1A2 and CYP2C6/11. Interestingly, neither inhibition nor induction on CYP3A was observed for CSBTA. In conclusion, CSBTA–drug interactions might occur through CYP450s inhibition, particularly CYP1A and CYP2D. Further studies are still needed to elucidate the underlying mechanisms of inhibition.     

Impact of Tetrahydropalmatine on the Pharmacokinetics of Probe Drugs for CYP1A2, 2D6 and 3A Isoenzymes in Beagle Dogs

Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open‐label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non‐compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC_{0–24 h} and decreased AUC_{ratio(0–24 h)} (1‐hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC_{0–24 h} and 29% or 22 decrease for AUC_{ratio(0–24 h),} respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A‐mediated herb–drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.     

清开灵注射液对大鼠CYP1A2和2D6的影响

目的：通过清开灵注射液的大鼠体内、外实验,观察清开灵注射液对大鼠CYP1A2亚型,CYP2D6亚型的影响。方法：通过HPLC法测定全血中咖啡因的代谢率,观测清开灵注射液对大鼠CYP1A2活性的影响；通过HPLC法测定大鼠肝微粒体重组系统非那西丁的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP1A2亚型的作用；测定大鼠肝微粒体重组系统右美沙芬的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP2D6亚型的作用。结果：实验组中给予大鼠不同浓度的清开灵注射液(0.15,0.3,0.6 mL·kg^-1),其咖啡因代谢率为(15.9±3.8)%,(14.5±1.8)%,(12.3±1.2)%,对照组为(16.8±5.9)%,各剂量组及对照组间均无显著性差异；肝微粒体体外重组系统中,实验组各浓度清开灵注射液对CYP2D6没有影响；高剂量组清开灵注射液对CYP1A2有抑制作用。结论：清开灵注射液对CYP1A2和 CYP2D6的活性没有影响。     

In vitro Inhibition of CYP3A4 by the Multiherbal Commercial Product Sambucus Force and its Main Constituents Echinacea purpurea and Sambucus nigra

The multiherbal product Sambucus Force contains Echinacea purpurea and Sambucus nigra as its main constituents. The aims of this study were to evaluate Sambucus Force's inhibition potential and inhibition mechanisms towards CYP3A4, and to evaluate the inhibitory co‐contribution of E. purpurea and S. nigra. Metabolic studies were performed with recombinant human CYP3A4, with testosterone as substrate. Sambucus Force inhibited CYP3A4 activity with a mean (95% confidence interval) half maximal inhibitory concentration (IC₅₀) value of 1192 (1091–1302) µg/mL. The inhibitory potency seems exclusively to be exerted by E. purpurea, implicating an insignificant inhibition by S. nigra. The inhibition by E. purpurea as a single herb was in agreement with mechanism‐based inhibition with heterotropic positive cooperative effects. Echinacea purpurea acted differently in the multiherbal product, which showed a dual inhibition profile with both an uncompetitive (substrate‐dependent) inhibition and a time‐dependent (substrate‐independent) inhibitory mechanism. These mechanistic differences are suggested to be caused by herb–herb interactions in the multiherbal product. The CYP3A4 inhibition of Sambucus Force in vitro is considered relatively weak, but recommended high herbal dosages might enhance the potential for clinical interactions. Copyright © 2012 John Wiley & Sons, Ltd.     

Effects of Vernonia cinerea Compounds on Drug‐metabolizing Cytochrome P450s in Human Liver Microsomes

Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide‐type sesquiterpene lactones, have shown an inhibition effect on the nicotine‐metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC‐MS/MS analysis. Among tested flavonoids, chrysoeriol was more potent in inhibition on CYP2A6 and CYP1A2 than other liver CYPs, with better binding efficiency toward CYP2A6 than CYP1A2 (K_i values in competitive mode of 1.93 ± 0.05 versus 3.39 ± 0.21 μM, respectively). Hirsutinolides were prominent inhibitors of CYP2A6 and CYP2D6, with IC₅₀ values of 12–23 and 15–41 μM, respectively. These hirsutinolides demonstrated time‐dependent inhibition, an indication of mechanism‐based inactivation, toward CYP2A6. Quantitative prediction of microsomal metabolism of these flavonoids and hirsutinolides, including half‐lives and hepatic clearance rate, was examined. These findings may have implications for further in vivo studies of V. cinerea. Copyright © 2017 John Wiley & Sons, Ltd.     

利血平诱导的急性抑郁模型大鼠体内CYP450亚酶的活性变化

目的:运用Cocktail探针法测定利血平诱导的急性抑郁模型大鼠体内6种细胞色素P450(CYP450)亚酶活性变化,从药物代谢相互作用的角度探寻抑郁症的发病机制。方法:建立利血平诱导的急性抑郁模型,大鼠随机分为空白组(记为A组),模型组(记为C组)和西药文拉法辛组(记为H组),适应1星期后,H组连续给药2周,A组和C组给予清水2周,第21天C组和H组按4 mg·kg~(-1)腹腔注射利血平注射剂,A组注射等体积生理盐水,第22天禁食不禁水12 h,第23天各组大鼠按10 m L·kg~(-1)灌胃给予混合探针药物。选取茶碱、氯唑沙宗、甲苯磺丁脲、右美沙芬、奥美拉唑以及咪达唑仑作为大鼠CYP1A2,CYP2C6,CYP2D1,CYP2D2,CYP2E1和CYP3A2的探针底物,采用LC-MS/MS测定大鼠体内6种混合探针的血药浓度,计算药动学参数。结果:造模后甲苯磺丁脲在大鼠体内浓度显著升高、代谢减慢;咪达唑仑在大鼠体内浓度显著降低、代谢加快。给予抗抑郁文拉法辛后,茶碱、氯唑沙宗和咪达唑仑在大鼠体内浓度显著升高、代谢减慢。结论:利血平诱导的急性抑郁模型状态对大鼠CYP2D1和CYP2D2有中强抑制作用,对CYP3A2有中强诱导作用;给予文拉法辛后对模型大鼠CYP1A2,CYP2C6,CYP2E1,CYP3A2为中强抑制作用。     

甘草化学成分与细胞色素P450酶间的相互作用研究进展

甘草Glycyrrhizae Radix为豆科植物乌拉尔甘草Glycyrrhiza uralensis、胀果甘草Glycyrrhiza inflata或光果甘草Glycyrrhiza glabra的干燥根或根茎,在临床上常与其他药物联合使用。结合国内外最新研究进展,总结了甘草的主要化学成分与细胞色素P450酶(CYP450)之间的相互作用,包括:(1)CYP酶参与甘草化学成分的代谢过程;(2)甘草化学成分对CYP酶活性的抑制或诱导作用研究;(3)甘草-临床药物联合使用引发潜在的草药-药物相互作用。深入研究甘草的化学成分与主要药物代谢酶之间的相互作用,对于指导中药复方的增效减毒、配伍,以及避免临床草药-药物相互作用等具有重要意义。     

Inhibitory effects of curcumenol on human liver cytochrome P450 enzymes

Curcumenol, one of the major components of Zedoary turmeric oil, has been widely used to treat cancer and inflammation. As an antibiotic or anticancer drug, curcumenol is highly likely to be used in combination with various synthetic drugs in most cases, thus it is necessary to evaluate potential pharmacokinetic drug‐drug interactions induced by curcumenol. In this study, the inhibitory effects of curcumenol on seven CYP isoforms were investigated, and the results demonstrated that only CYP3A4 was strongly inhibited (IC₅₀ = 12.6 ± 1.3 μM). Kinetic analysis showed the inhibition type was competitive with K_i value of 10.8 μM. Time‐ and NADPH‐dependent inhibitions were also investigated to show curcumenol is not a mechanism‐based inhibitor. Employing these in vitro data and maximum plasma concentration of curcumenol in human predicted from beagle dog's in vivo pharmacokinetic data, the change in AUC of victim drugs was predicted to be 0.4%, which suggested that curcumenol may be safely used without inducing metabolic drug‐drug interaction through P450 inhibition. Nevertheless, due to the limited pharmacokinetic data available for curcumenol in humans, it is still not possible to evaluate its potential clinical effects on human patients from in vitro data. Thus, the magnitude of drug‐drug interaction (DDI) induced by curcumenol warrants further investigation. Copyright © 2010 John Wiley & Sons, Ltd.     

In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients

The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P‐450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c‐DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6‐β‐OH‐testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC₅₀: 73 µg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 µg/mL, respectively). All IC₅₀ values were high compared with those determined for crude extracts of other herbal remedies. The IC₅₀/IC₂₅ ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non‐inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright © 2009 John Wiley & Sons, Ltd.