• KSBB Journal
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• v.15 no.4
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• pp.331-336
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• 2000

The antimutagenic activity of the extract of Artemisia capillaris THUNB on the mutagenicity induced by benzo(a)pyrene [B(a)P] in the presense of S9 mixture was studied using bacterial mutagenic assay system. Samples harvested in summer and autumn were extracted using ethanol and hot water. Among these extracts the water extract of summer sample had the strongest inhibitory effect against the mutagenenicity of B(a)P, The water extract of Artemisia capillaris THUNB was separated again into ethanol soluble and insoluble parts. The ethanol insoluble part(El) of water extract exhibited higher inhibition effects than the ethanol soluble part against the mutagenic activity of B(a)P. El showed dose-dependent activity on the mutagenicity of B(a)P in SOS Chromotest and Ames test. The 50% inbibition concentraction $(IC_{50}$ of El were $200{\mu}g/assay$ $600{\mu}g/plate$ and $800{\mu}b/plate$ in E. coil PQ37 S. typhimurium TA100 and TA98 respectively. El were showed desmutagenic effect but had no effect on the DNA repair system for B(a)P-induced mutagenesis. HPLC analysis showed that the formation of aflatoxin M1 by cytochrome P-450 1A1 known as playing an impotant role on B(a) P-induced mutagenicity was highly inhibited by El. Therefore we encluded that B(a)P-induced mutagencity can be reduced possible due to the interference of el with cytochrome P-450 1A1-dependent bioactivation.

• Biomolecules & Therapeutics
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• v.18 no.3
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• pp.343-349
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• 2010

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $25.2\;{\mu}M$. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration ($C_{max}$) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

• Biomolecules & Therapeutics
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• v.19 no.4
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• pp.493-497
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• 2011

The aim of this study was to investigate the effect of amlodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of amlodipine (0.1 or 0.4 mg/kg) in rats. The effect of amlodipine on the P-glycoprotein (P-gp) as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Amlodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 9.1 ${\mu}M$. Compared to those animals in the oral control group (warfarin without amlodipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (0.1 mg/kg, p<0.05; 0.4 mg/kg, p<0.01) by 26.5-53.5%, and the peak plasma concentration ($C_{max}$) was significantly higher (0.4 mg/kg, p<0.05) by 26.2% after oral administration of warfarin with amlodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.26- to 1.53-fold and the absolute bioavailability of warfarin with amlodipine was significantly greater by 61.7-72.5% compared to that in the control group (47.4%). In contrast, amlodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver rather than renal elimination and P-gp by amlodipine.

• YAKHAK HOEJI
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• v.47 no.2
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• pp.98-103
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• 2003

The purpose of this study was to investigate the effect of flavone (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with flavone was increased significantly (coadministration p＜0.05, pretreatment p＜0.0l) compared to that of control. Area under the plasma concentration-time curve (AVC) of paclitaxel with flavone was significantly (coadministration p＜0.05, pretreatment p＜0.0l) higher than that of control. Peak concentration (Cmax) of paclitaxel with flavone were significantly increased (coadministration p＜0.05, pretreatment p＜0.01) compared to that of control. Time to peak concentration (Tmax) of paclitaxel with flavone decreased significantly (p＜0.05) than that of control. The total body clearance (CLt) and elimination rate constant ($\beta$) of paclitaxel with flavone were significantly reduced (p＜0.05) compared to those of control. Half-life (t$_{1}$2/) of paclitaxel with flavone was significantly prolonged (p＜0.05) compared to that of control. Based on these results, it might be concluded that flavone may enhance bioavailability of paclitaxel through the inhibition of cytochrome P450 and P-glycoprotein, which are engaged in paclitaxel absorption and metabolism in liver and gastrogintestinal mucosa, respectively.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.1
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• pp.83-91
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• 1999

Angiotensin II (ANG II) has a biphasic effect on $Na^+$ transport in proximal tubule: low doses of ANG II increase the $Na^+$ transport, whereas high doses of ANG II inhibit it. However, the mechanisms of high dose ANG II-induced inhibition on $Na^+$ uptake are poorly understood. Thus the aim of the present study was to investigate signal transduction pathways involved in the ANG II-induced inhibition of $Na^+$ uptake in the primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. ANG II $(10^{-9}\;M)-induced$ inhibition of $Na^+$ uptake was blocked by losartan $(10^{-8}\;M,\;AT_1\;antagonist),$ but not by PD123319 $(10^{-8}\;M,\;AT_2\;antagonist)$ (P<0.05). ANG II-induced inhibition of $Na^+$ uptake was also completely abolished by neomycin $(10^{-4}\;M,$ PLC inhibitor), W-7 $(10^{-4}\;M,$ calmodulin antagonist), and $AACOCF_3\;(10^{-6}\;M,\;PLA_2\;inhibitor)$ (P<0.05). ANG II significantly increased $[^3H]arachidonic$ acid (AA) release compared to control. The ANG II-induced $[^3H]AA$ release was blocked by losartan, $AACOCF_3,$ neomycin, and W-7, but not by PD123319. ANG II-induced $[^3H]AA$ release in the presence of extracellular $Ca^{2+}$ was greater than in $Ca^{2+}-free$ medium, and it was partially blocked by TMB-8 $(10^{-4}\;M,$ intracelluar $Ca^{2+}$ mobilization blocker). However, in the absence of extracellular $Ca^{2+},$ it was completely blocked by TMB-8. In addition, econazole $(10^{-6}\;M,$ cytochrome P-450 monooxygenase inhibitor) and indomethacin $(10^{-6}\;M,$ cyclooxygenase inhibitor) blocked ANG II-induced inhibition of $Na^+$ uptake, but NGDA $(10^{-6}\;M,$ lipoxygenase inhibitor) did not affect it. In conclusion, $PLA_2-mediated$ AA release is involved in ANG II-induced inhibition of $Na^+$ uptake and is modulated by $[Ca^{2+}]_i$ in the PTCs.

• Archives of Pharmacal Research
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• v.12 no.3
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• pp.196-200
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• 1989

The methanolic extract of the Rhizome of Curcuma zedoaria exhibited a significant prolongation of hexobarbital (HB)-induced hypnosis. Through liquid chromatography of an ether soluble fraction. monitoring by bioassay, three sequiterpenes, germacrone (A), curzerenone (B) and germacrone epoxide (C) were isolated as active consituents. A single treatment (100-200 mg/kg, i.p.) of each compound showed not only a significant prolongation of HB-induced sleeping time but also a significant inhibition of aminopyrine N-demethylase activity in mice, and further exhibited a typical type I binding spectra with oxidized rat hepatic cytochrome P-450 induced by phenobarbital. All of the compounds provoked a sleep episode at a subhypnotic dose of HB, implying that they possess CNS depressant properties.

• Journal of Pharmaceutical Investigation
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• v.33 no.3
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• pp.223-227
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• 2003

The purpose of this study was to investigate the effect of ketoconazole (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with ketoconazole was significantly (p<0.05) increased from 8 hr to 24 hr compared to that of control. Area under the plasma concentration-time curve (AUC) of paclitaxel with ketoconazole was significantly (coadministration p<0.05, pretreatment p<0.0l) higher than that of control. Peak concentration $(C_{max})$ of paclitaxel pretreated with ketoconazole were significantly (p<0.05) increased compared to that of control. Time to peak concentation $(T_{max})$ of paclitaxel pretreated with ketoconazole were significantly (p<0.05) shorter than that of control. Half-life at elimination phase $(t_{1/2{\beta}})$ of paclitaxel pretreated with ketoconazole was significantly (p<0.05) prolonged compared to that of control. Based on these results, it might be due to both inhibition of the enzyme cytochrome P450 and p-glycoprotein, which engaged in paclitaxel absorption and metabolism in liver and gastrointestinal mucosa.

• Korean Journal of Environmental Biology
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• v.21 no.1
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• pp.18-25
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• 2003

Effects of tributyltin chloride (TBTC) in vitro on mixed function oxygenase (MFO) system on liver microsome of eight marine fish species were investigated. To determine the effects on MFO system, cytochrome P45O (CYP) and cytochrome b5 con-tents, activities of two reductases (NADH-cytochrome b5 reductase and NADPH-cy-tochrome P450 reductase) and four dealkylation enzymes (EROD, PROD, MROD and ECOD) were measured in fish microsoms exposed to TBTC for 20 min. The WP content was reduced to 10% of the control group in 6 out of 8 species exposed to TBTC, whereas there was no significant change in the cytochrome bs content. the response of NAD(P)H dependant reductases depended on fish species. The dealkylation enzyme activities in microsome were also apparently inhibited by TBTC. The degree of inhibition was different among fish species and four enzymes. The EROD activities in eight species were decreased to the range of 1∼65% of control group.

• Journal of Pharmaceutical Investigation
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• v.41 no.5
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• Journal of Pharmaceutical Investigation
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• v.38 no.5
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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.