• Journal of Pharmaceutical Investigation
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• 제36권5호
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• pp.315-320
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• 2006

Silymarin showed P-glycoprptein(P-gp) inhibitory activity as much as verapamil, a well-known P-gp inhibitor, by decreasing $IC_{50}$ value of daunomycin(DNM)($16.0{\pm}0.7{\mu}M$), increasing the DNM accumulation($224.9{\pm}3.2%$), and decreasing DNM efflux($58.5{\pm}6.7%$), concurrently. In this study, we clarified the mechanism of action of silymarin for P-gp inhibitory function. First, silymarin may bind to the ATP-binding site and thus, prevent ATP hydrolysis. Second, the P-gp inhibitory activity of silymarin is not related to changing the cellular P-gp level. Third, the cytotoxicity of silymarin was increased in the presence of verapamil, reflecting that silymarin is a competent P-gp substrate against verapamil in the P-gp-overexpressed adriamycin-resistant MCF-7 breast cancer(MCF-7/ADR) cells. Conclusively, silymarin had the P-gp inhibitory activity through the action of competent binding to the P-gp substrate-binding site. Therefore, silymarin can be a good candidate for safe and effective MDR reversing agent in clinical chemotherapy by administering concomitantly with anticancer drugs.

• 한국농림기상학회지
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• 제14권1호
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• pp.39-44
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• 2012

본 연구는 1963년도에 식재된 낙엽송, 소나무, 리기테다소나무 조림지를 대상으로 셀룰로오스 분해와 토양 환경인자 사이의 관계를 구명하기 위해 수행하였다. 셀룰로오스 분해에 영향을 미칠 수 있는 토양온도, 토양 수분함량, 토양 pH, 토양 이산화탄소 방출량을 2006년 7월부터 10월까지 4개월 동안 측정하였다. 셀룰로오스 분해율은 리기테다소나무($6.5mg\;g^{-1}\;day^{-1}$), 소나무($6.2mg\;g^{-1}\;day^{-1}$), 낙엽송($6.1mg\;g^{-1}\;day^{-1}$) 순이었으나 수종간 유의적인 차이는 없었다(P > 0.05). 셀룰로오스 분해율은 20cm 깊이의 토양 온도와 양의 상관(소나무: r = 0.77, P < 0.05; 리기테다소나무: r = 0.59, P < 0.05; 낙엽송: r = 0.48, P < 0.05)을 보였으나, 토양 pH와는 음의 상관(소나무: r = -0.63, P < 0.05; 리기테다소나무: r = -0.47, P < 0.05; 낙엽송: r = -0.43, P < 0.05)이 있었다. 토양이산화탄소방출량과 셀룰로오스 분해율은 소나무(r = 0.46, P < 0.05), 낙엽송(r = 0.37, P < 0.05), 토양 수분함량과 셀룰로오스 분해율은 소나무(r = 0.53, P < 0.05)와 유의적인 양의 상관(P < 0.05)이 있었다. 본 연구 결과에 따르면 셀룰로오스 분해는 각기 다른 침엽 수종으로부터 발생하는 토양 환경요인에 의해 영향을 받는 것으로 나타났다.

• Natural Product Sciences
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• 제20권1호
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• pp.1-6
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• 2014

P-glycoprotein (P-gp) is a permeability glycoprotein also known as multidrug resistance protein 1 (MDR1). P-gp is an ATP-binding cassette (ABC) transporter that pumps various types of drugs out of cells. These transporters reduce the intracellular concentrations of drugs and disturb drug absorption. The Caco-2 cell permeability assay system is an effective in vitro system that predicts the intestinal absorption of drugs and the functions of enzymes and transporters. Rhodamine-123 (R-123) and digoxin are well-known P-gp substrates that have been used to determine the function of P-gp. Efflux of P-gp substrates by P-gp has been routinely evaluated. To date, a number of herbal medicines have been tested with Caco-2 cell permeability assay system to assess bioavailability. There are growing efforts to find phytochemicals that potentially regulate P-gp function. The Caco-2 cell permeability assay system is a primary strategy to search for candidates of P-gp inhibitors. In this mini review, we have summarized the P-gp modulation by herbal extracts, decoctions or single components from natural products using Caco-2 cell permeability assays. Many natural products are known to regulate P-gp and herbal medicines could be used in combination with conventional drugs to enhance bioavailability.

• Journal of Pharmaceutical Investigation
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• 제35권2호
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• pp.101-106
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• 2005

The pharmacokinetics of oral nifedipine (5 mg/kg) was studied in rabbits given after or simultaneously with naringin (1.5, 7.5 and 15 mg/kg, respectively). The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of nifedipine coadministered or pretreated with naringin were significantly increased (p < 0.05, coad.; p < 0.01, pret.) compared with the control group. The absolute bioavailability (AB%) of nifedipine was significantly (p < 0.05, coad.; p < 0.01, pret.) higher by 22.3 - 28.1 % compared to the control (17.9%). The relative bioavailability (RB%) of nifedipine was higher by 1.24 - 1.43 times (coad.) and 1.32 -1.57 times (pret.) than those of the control, showing that preatreatrnent of naringin was more effective than that of the coadministration of naringin. Naringin did not show significant effect on the Tmax and $t_{1/2}$ of nifedipine. It is suggested that naringin may alter pharmacokinetic paramiters of nifedipine by inhibition of P-glycoprotein efflux pump and its first-pass metabolism. The dosage of nifedipine should be adjusted when it is administered with naringin in a clinical situation.

• Journal of Pharmaceutical Investigation
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• 제38권5호
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• pp.313-317
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• 2008

This study investigated the effect of naringin, a flavonoid, on the bioavailability of etoposide administered orally to rats. Etoposide (6 mg/kg) was administered orally to rats alone or with naringin (1, 4 or 12 mg/kg). Compared with the control group, the co-administration of etoposide with 4 and 12 mg/kg of naringin significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) and the peak plasma concentration ($C_{max}$) of the oral etoposide. Consequently, the absolute bioavailability (AB) of etoposide in the presence (4 and 12 mg/kg) of naringin was significantly (p<0.05) increased by $9.4{\sim}10.6%$ compared with the control group (7.4%). The relative bioavailability (RB) of etoposide was increased 1.13- to 1.44-fold compared to the control group. Enhanced bioavailability of etoposide might be due to inhibition of both cytochrome P450 (CYP) 3A4 in the intestine or liver and P-glycoprotein (P-gp) transport efflux of etoposide in the intestinal membrane. This data indicate that careful consideration of the dosage for therapy with etoposide is required in a case of clinical application of the co-administration of etoposide and naringin.

• Journal of Pharmaceutical Investigation
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• 제40권5호
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• pp.269-275
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• 2010

P-gp plays a critical role in drug disposition and represents a mechanism for the development of multidrug resistance. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to inhibit P-gp. Therefore, the aim of this study was to identify new candidate chemosensitizers by screening various plant extracts. The ability of natural plant extracts to inhibit P-gp activity was assessed by measuring cellular accumulation of calcein AM, daunorubicin and vincristine in P-gp overexpressing MDCKII-MDR1 cells. Among more than 800 plant extracts, eight were found to inhibit P-gp activity. Curcuma aromatica extract produced greatest inhibition, followed by Curcuma longa and Dalbergia odorifera extracts. Extracts of Aloe ferox, Curcuma zedoariae rhizome, Zanthoxylum planispinum, and Ageratum conyzoides showed moderate inhibitory effects. Curcumin and quercetin exhibited similar inhibition of P-gpmediated efflux of daunorubicin and vincristine, and flavones had a lesser effect. When chemosensitizing effect was evaluated by measuring daunorubicin sensitivity to MDCKII-MDR1 cells in the presence of natural plant extracts, Curcuma aromatica showed the most potent chemosensitizing effect based on daunorubicin cytotoxicity. In conclusion, natural plant extracts such as Curcuma aromatica can potently inhibit P-gp activity and may have potential as a novel chemosensitizers.

• Molecules and Cells
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• 제37권6호
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• pp.441-448
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• 2014

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multiprotein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-$1{\beta}$ and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-${\kappa}B$-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 ($P2X_7R$), which results in $K^+$ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

• 약학회지
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• 제51권3호
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• pp.169-173
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• 2007

The aim of this study was to investigate the effect of morin on the pharmacokinetics of nifedipine in rats. The pharmacokinetic parameters of nifedipine were measured after the oral administration of nifedipine (5 mg/kg) in the presence or absence of morin (1.5, 7.5 and 15 mg/kg, respectively). Compared to the control groups, the presence of 7.5 mg/kg and 15 mg/kg of morin significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of nifedipine by 48.5${\sim}$68.2%, and the peak concentration (C$_{max}$,) of nifedipine by 59.9~84.2%. The absolute bioavailability(AB%) of nifedipine was significantly (p<0.05) increased by 21.5${\sim}$24.5% compared to the control (14.5%). While there was no significant change in the time to reach the peak plasma concentration (T$_{max}$) and the terminal half-life (T$_{1/2}$) of nifedipine in the presence of morin. It might be suggested that morin altered disposition of nifedipine by inhibition of both the first-pass metabolism and p-glycoprotein (P-gp) efflux pump in the small intestine of rats. In conclusion, the presence of morin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of morin or morin-containing dietary supplement with nifedipine should require close monitoring for potential drug interaction.

• Archives of Pharmacal Research
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• 제29권11호
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• pp.1018-1023
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• 2006

Chemoresistance remains the major obstacle to successful therapy of cancer. In order to understand the mechanism of multidrug resistance (MDR) that is frequently observed in lung cancer patients, here we studied the contribution of MDR-related proteins by establishing lung cancer cell lines with acquired resistance against etoposide. We found that human H460 lung cancer cells responded to etoposide more sensitively than A549 cells. Among MDR-related proteins, the expression of p-glycoprotein (Pgp) and lung resistance protein (LRP) were much higher in A549 cells compared with that in H460 cells. When we established H460-R1 and -R2 cell lines by progressive exposure of H460 cells to increasing doses of etoposide, the response against etopbside as well as doxorubicin was greatly reduced in R1 and R2 cells, suggesting MDR induction. Induction of MDR was not accompanied by a decrease in the intracellular accumulation of etoposide and the expression of MDR-related proteins that function as drug efflux pumps such as Pgp and MRP1 was not changed. We found that the acquired resistance paralleled an increased expression of LRP in H460 cells. Taken together, our data suggest the implicative role of LRP in mediating MDR in lung cancer.

• 약학회지
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• 제54권5호
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• pp.370-376
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• 2010

The aim of this study is to investigate the effect of apigenin on the pharmacokinetics of tamoxifen in rats. Tamoxifen was administered orally (10 mg/kg) or intravenously (2 mg/kg) without or with oral administration of apigenin (0.4, 2.0 or 8.0 mg/kg) to rats. The effect of apigenin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Apigenin inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The plasma concentrations of tamoxifen were increased significantly by apigenin compared to control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations ($IC_{max}$) of tamoxifen with apigenin were significantly higher than those of the control group. Consequently, the relative bioavailability (RB%) of tamoxifen with apigenin was 2-3-fold higher than the control, and absolute bioavailability (AB%) of tamoxifen were significantly higher (p<0.05 with co-administration, p<0.01 with pretreatment) than those of the control. The increased bioavailability of tamoxifen in rats with apigenin might be associated with the inhibition of an efflux pump P-glycoprotein and CYP3A4 by apigenin. From these results, dosage regimen of tamoxifen may be need to adjust when concomitantly administered with apigenin.