The Inhibitory Effect of 20(S)‐Protopanaxatriol (ppt) Towards UGT1A1 and UGT2B7

Ginseng, a commonly used natural product, has been frequently reported to induce herb–drug interaction with many clinical drugs. The intestinal bacterial metabolites of ginsenosides have been widely regarded as the substance basis for ginseng–drug interactions. To date, little is known about the inhibitory effect of intestinal bacterial metabolites of ginsenosides towards UDP‐glucuronosyltransferases (UGTs). In vitro investigation of the inhibition of 20(S)‐protopanaxatriol (ppt) towards UGT1A1 and UGT2B7 was carried out. The results showed that ppt exhibited strong noncompetitive inhibition towards UGT1A1 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters (K_i) were calculated to be 8.8 and 2.2 μM for UGT1A1 and UGT2B7, respectively. Using the maximum plasma concentration of ppt, the alteration of area under the concentration–time curve was calculated to be 20% and 70% respectively for UGT1A1‐mediated and UGT2B7‐mediated metabolism. However, given that the varied contribution of these two UGT isoforms towards drug metabolism and the influence of herb complexity and individual difference, the explanation of these results should be paid more caution. Copyright © 2012 John Wiley & Sons, Ltd.     

Herb–drug interaction studies of herbs used in treatment of cardiovascular disorders—A narrative review of preclinical and clinical studies

About 70% of the world population is currently using medicinal herbs as complementary or alternative medicine, which is increasing at a tremendous pace in both developed and developing countries in the last two decades (World Health Organization Medicines Strategy 2002–2005). This increase in consumer demand of medicinal herbs continues despite the rarity of scientific data to establish their safety and efficacy profile. Its popularity is also attributed to several factors, including easy availability, cost effectiveness leading to better purchasing power and general perception that they are safe. Herbs are often administered concomitantly with therapeutic drugs for the treatment of major ailments, raising the potential for herb–drug interactions (HDIs). The major pathways postulated for HDIs involves the cytochrome P450 (CYP450)‐mediated inhibition or induction and transport and efflux proteins. In our review, we highlight frequently used herbal medicines for the treatment of cardiovascular disorders (CVD), their established HDIs studied using in vitro tools and in vivo pharmacokinetic and pharmacodynamic assays and case reports. Herbs have been divided into different sections on the basis of availability of HDI data in relevance to cardiovascular drugs: herbs reported to interact with cardiac drugs, herbs yet to be reported for interaction with drugs of any class and herbs reported to interact with drugs of other therapeutic category but not with cardiac drugs. The amount of active phytoconstituents present in the selected herbs and their extent of bioavailability are also mentioned. This review can serve as a quick reference database for physicians and health care professionals involved in CVD treatment, aimed at maximizing clinical outcomes with reduction in adverse and toxic effects.     

Pharmacokinetic Herb–Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice

Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb–drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography–mass spectrometry) of aniseed EO has confirmed trans‐anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 ± 32% vs. 85 ± 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 ± 24% vs. 101 ± 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered. Copyright © 2015 John Wiley & Sons, Ltd.     

Identification of cytochrome P450 (CYP) isoforms involved in the metabolism of corynoline,and assessment of its herb–drug interactions

Corynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity. The present study focused on its metabolism and metabolism‐based herb–drug interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two metabolites (M‐1 and M‐2) were formed. Chemical inhibition experiments and assays with recombinant CYP isoforms showed that CYP2C9 was mainly involved in the formation of M‐1 and CYP3A4 mainly catalysed the production of M‐2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC₅₀ of 3.3 ± 0.9 µm and 31.5 ± 0.5 µm , respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with K_i of 3.2 µm , while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with K_i of 6.3 µm . Additionally, corynoline exhibited time‐dependent inhibition (TDI) toward CYP3A4. The inactivation kinetic parameters (K_I and k_inact) were calculated to be 6.8 µm and 0.07 min^‐1, respectively. These data are of significance for the application of corynoline and corynoline‐containing herbs. Copyright © 2010 John Wiley & Sons, Ltd.     

Catalpol provides a protective effect on fibrillary Aβ1–42‐induced barrier disruption in an in vitro model of the blood–brain barrier

Excessive amyloid beta (Aβ) deposition in brain is mainly responsible for cell damage and blood–brain barrier (BBB) disruption in Alzheimer's disease (AD). Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch, has neuroprotective effect against AD. It is unclear whether catalpol has a protective effect on Aβ‐induced BBB leakage. We employed an immortalized endothelial cell line (bEnd.3) and astrocytes co‐culture to mimic a BBB model in vitro and investigated the effect of catalpol on BBB. We found that treatment with catalpol decreased BBB hyperpermeability induced by fibrillar Aβ_1–42. Data from western blotting showed that catalpol prevented fibrillar Aβ_1–42‐induced bEnd.3 cell apoptosis through mitochondria‐dependent and death receptor pathways; decreased the levels of matrix metalloproteinases (MMPs), MMP‐2, MMP‐9, and the receptor for advanced glycation end products; and increased the levels of tight junction proteins (ZO‐1, occludin, and claudin‐5), low‐density lipoprotein receptor‐related protein 1, and P‐glycoprotein in fibrillar Aβ_1–42‐treated bEnd.3 cells. Moreover, catalpol also enhanced soluble Aβ efflux across the fibrillar Aβ_1–42‐treated bEnd.3 cells BBB monolayer model. Altogether, our results suggest that catalpol alleviate fibrillar Aβ_1–42‐induced BBB disruption, enhance soluble Aβ clearance, and offer a feasible therapeutic application in AD treatment.     

Genistein inhibits Aβ25–35‐induced SH‐SY5Y cell damage by modulating the expression of apoptosis‐related proteins and Ca2+ influx through ionotropic glutamate receptors

In this study, we investigated the protective effects of genistein against SH‐SY5Y cell damage induced by β‐amyloid 25–35 peptide (Aβ_25–35) and the underlying mechanisms. Aβ‐induced neuronal death, apoptosis, glutamate receptor subunit expression, Ca²⁺ ion concentration, amino acid transmitter concentration, and apoptosis‐related factor expression were evaluated to determine the effects of genistein on Aβ‐induced neuronal death and apoptosis. The results showed that genistein increased the survival of SH‐SY5Y cells and decreased the level of apoptosis induced by Aβ_25–35. In addition, genistein reversed the Aβ_25–35‐induced changes in amino acid transmitters, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptors, and N‐methyl‐d ‐aspartate (NMDA) receptor subunits in SH‐SY5Y cells. Aβ_25–35‐induced changes in Ca²⁺ and B‐cell lymphoma‐2 (Bcl‐2) and Bcl‐2‐associated X (Bax) protein and gene levels in cells were also reversed by genistein. Our data suggest that genistein protects against Aβ_25–35‐induced damage in SH‐SY5Y cells, possibly by regulating the expression of apoptosis‐related proteins and Ca²⁺ influx through ionotropic glutamate receptors.     

Protective effect of Morinda citrifolia fruits on β‐amyloid (25–35) induced cognitive dysfunction in mice: An experimental and biochemical study

The neuroprotective effect of an ethyl acetate extract of Morinda citrifolia (Rubiaceae) Linn. fruits (EMC, ethyl acetate extract of Morinda citrifolia) at doses of 200 and 400 mg/kg, p.o. was studied on β‐amyloid (25–35) peptide induced cognitive dysfunction in mice. In the step‐down inhibitory avoidance, EMC exhibited a significant increase in short‐term memory and long‐term memory (p < 0.05). A significant decrease (p < 0.01) in escape latency was noticed in the animals in the water maze. A significant increase (p < 0.01) in alteration of behavior was exhibited upon administration of EMC 200 and 400 mg/kg on the Y maze. Exploratory parameters such as line crossings, head dipping and rearing were increased significantly in EMC treated groups in a dose‐dependent manner (p < 0.05 and p < 0.01). A significant reduction (p < 0.05) in acetyl cholinesterase activity was noticed in the EMC 200 and 400 mg/kg treated groups. The level of monoamine oxidase‐A was decreased by the administration of EMC 200 and 400 mg/kg (p < 0.05 and p < 0.01, respectively). EMC at a dose of 400 mg/kg exhibited a significant increase (p < 0.01) in the levels of serotonin and dopamine. Antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase and ascorbic acid were decreased significantly in the b‐amyloid peptide injected group, whose levels were restored significantly (p < 0.01) by the administration of EMC (400 mg/kg). Copyright © 2009 John Wiley & Sons, Ltd.