• 한국임상약학회지
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• 제21권3호
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• pp.215-223
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• 2011

암로디핀과 레파그리니드의 병용은 당뇨병의 합병증으로인한 고혈압 유발 시 병용 처방될 수 있다. 암로디핀과 레파그리니드의 약동학적 상호작용 연구를 위하여 암로디핀 (0.1 및 0.4 mg/kg) 과 레파그리니드를 흰 쥐에 경구(0.5 mg/kg) 및 정맥 (0.2 mg/kg) 투여하여 연구를 실시하였다. 암로디핀이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 암로디핀의 CYP3A4의 50% 효소활성억제는 $9.1{\mu}M$ 이었다. 암로디핀은 P-gp의 활성에는 영향을 미치지 않았다. 암로디핀 (0.4 mg/kg)은 레파그리니드의 혈장곡선하면적(AUC)과 최고혈장농도 ($C_{max}$)를 40.2% 와 22.2% 각각 유의성 (p < 0.05)있게 증가시켰다. 따라서, 레파그리니드의 상대적생체이용률 (RB)은 암로디핀과 병용투여 시 1.18-1.40 배 증가되었으며, 또한 레파그리니드의 절대적생체이용률(AB)은 대조군과 비교하여 41.0% 유의성 있게 증가되었다. 경구 투여 시와는 대조적으로, 암로디핀은 정맥 내로 투여된 레파그리니드에서는 약동학적 파라미터에 어떤 영향도 미치지 않았다. 따라서 암로디핀이 레파그리니드의 생체이용률을 증가시킨 것은 신장배설 감소 또는 P-gp 활성억제 보다는 암로디핀이 소장 또는 간장에서 CYP3A4을 억제시켰기 때문으로 사료된다. 암로디핀과 레파그리니드의 병용투여 시 레파그리니드의 용량을 조절하는 것이 안전하다고 사료된다.

• 약학회지
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• 제54권4호
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• pp.252-257
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• 2010

The aim of this study was to investigate the effect of resveratrol on the pharmacokinetics of nifedipine in rats. The pharmacokinetic parameters of nifedipine were measured after the oral administration of nifenipine (6 mg/kg) in the presence or absence of resveratrol (0.5, 2.5 and 10 mg/kg, respectively). The effect of resveratrol on the P-glycoprotein (Pgp), CYP 3A4 activity was also evaluated. Resveratrol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 0.94 ${\mu}M$. In addition, resveratrol significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared to the control groups, the presence of 2.5 mg/kg and 10 mg/kg of resveratrol significantly (p<0.05, p<0.01) increased the area under the plasma concentrationtime curve (AUC) of nifedipine by 49~75%, and the peak concentration ($C_{max}$) of nifedipine by 48~66%. The absolute bioavailability (AB%) of nifedipine was significantly (p<0.05) increased by 22.9-34.8% compared to the control (19.8%). The terminal half-life ($T_{1/2}$) of nifedipine was significantly (p<0.05) increased compared to the control. While there was no significant change in the time to reach the peak plasma concentration ($T_{max}$) of nifedipine in the presence of resveratrol. It might be suggested that resveratrol altered disposition of nifedipine by inhibition of both the CYP3A and P-glycoprotein efflux pump in the small intestine of rats. In conclusion, the presence of resveratrol significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of resveratrol or resveratrol-containing dietary supplenment with nifedipine should require close monitoring for potential drug interation.

• Biomolecules & Therapeutics
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• 제18권2호
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• pp.226-232
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• 2010

The aim of this study was to investigate the effect of atrovasatatin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine to rats. Nicardipine was administered orally (12 mg/kg) or intravenously (i.v., 4 mg/kg) without or with oral administration of atrovasatatin (0.3 or 1.0 mg/kg) to rats. The effect of atorvastatin on the P-glycoprotein (P-gp) as well as CYP3A4 activity was also evaluated. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 48 ${\mu}M$. Compared to the controls (nicardipine alone), the area under the plasma concentration-time curve (AUC) of nicardipine was significantly (1.0 mg/kg, p<0.05) greater by 16.8-45.4%, and the peak plasma concentration ($C_{max}$) was significantly (1.0 mg/kg, p<0.05) higher by 28.0% after oral administration of nicardipine with atorvastatin, respectively. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.17- to 1.45-fold and the absolute bioavailability (A.B.) of nicardipine with atrovasatatin was significantly greater by 16.7-20.9% compared to that of the controls (14.3%). Compared to the i.v. control, atrovasatatin did not significantly change pharmacokinetic parameters of i.v. administration nicardipine. The enhanced oral bioavailability of nicardipine by atorvastatin suggests that CYP3A subfamily-mediated metabolism were inhibited in the intestine and/or in the liver rather than P-gp-mediated efflux of nicardipine. Based on these results, modification of nicardipine of dosage regimen is required in the patients. Human studies are required to prove the above hypothesis.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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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.

• Biomolecules & Therapeutics
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• 제19권4호
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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.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2001년도 Korean Environmental Mutagen Society
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• pp.198-198
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• 2001

• 대한임상약리학회:학술대회논문집
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• 대한임상약리학회 2003년도 제12차 추계학술대회
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• pp.14-14
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• 2003

• 대한임상약리학회:학술대회논문집
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• 대한임상약리학회 1998년도 제7차 추계학술대회 및 정기총회
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• pp.60-60
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• 1998

• Environmental Analysis Health and Toxicology
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• 제21권2호
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• pp.127-138
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• 2006

In urban areas, diesel exhaust particles (DEP) are probably a major component of particulate matters, especially in Korea where drive many diesel vehicles. The aim of this study was to investigate genotoxic effects of DEP using single ceil gel electrophoresis. In order to evaluate the mechanisms of DEP genotoxicity, the rat microsome mediated and DNA repair enzyme treated comet assays together with conventional comet assay were performed. Total diesel particles (DEPT) was collected without site fractionation from diesel engine bus and dichloromethane extract was obtained. The organic extract of DEPT revealed DNA damage itself in NIH/3T3 cells. The level of DNA breaks plus oxidative DNA lesions and microsome mediated DNA damage was assessed by modified single cell gel eletrophoresis. DEPT was able to induce oxidative DNA damage as well as microsome mediated DNA damage. Vitamin C as an model antioxidant reduced DNA damage in endonuclase III treated comet assay. One of flavonoid, galangin as a CYP1A1 inhibitor. reduced DNA damage in the presence of S-9 mixture. $DEP_T$ is the sources of oxidative stress, but antioxidants can significantly reduce oxidative DNA dmage. And $DEP_T$ may contain indirect mutagens which can be inhibited by CYP1A1 inhibitors. The ethanol extracts of the mixed vegetables (BV) or the mixed fruits (BF) were evaluated for their in vitro antigenotoxic effects. BV and BF showed potent Inhibitory effects against DEPT induced DNA damage with oxidative DNA lesions and in the prescence of S-9 mixture. These results indicate that BV and BF could prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P4501A1 in cell culture.

• 한국식품영양과학회지
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• 제41권8호
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• pp.1106-1111
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• 2012

본 연구는 식이 불포화지방산으로 산화 스트레스가 유도된 쥐에게서 비타민 E의 항산화 효과를 알아보기 위해 4주령의 쥐 90마리를 1주일간 적응시킨 후, 정상식이를 섭취한 대조군(C), 식이 불포화지방산(올레산, 리놀레산, 리놀렌산, DHA)군, 식이 불포화지방산에 비타민 E를 첨가한 군으로 나누어 8주간 실시하였다. 체중변화는 대조군에 비하여 모든 군에서 증가하였고, 비타민 E 첨가군에서는 LA+비타민 E군을 제외한 모든 군에서 유의적인 체중증가가 나타났다. 뇌 마이크로좀의 지질과산화물 생성은 대조군에 비해 특히 LA, DHA 군에서 유의적으로 높은 경향을 보였다. 비타민 E 첨가 시 모든 군에서 첨가하지 않은 군에 비하여 지질과산화물 농도가 감소하였다. 뇌 세포질의 항산화 효소 SOD, GPx는 대조군에 비하여 모든 지방산 군에서 활성이 증가하였고 비타민 E 첨가 시 활성이 유의하게 감소하였다. 뇌 마이크로좀의 CYP2E1의 활성은 LNA군에서만 유의적으로 증가하고 비타민 E 첨가 시 LNAE군만이 유의하게 감소됨을 확인하였다. 이상의 실험결과, 식이 불포화지방산으로 유도된 뇌의 산화 스트레스는 비타민 E를 식이 불포화지방산과 같이 섭취함으로써 산화 스트레스 감소에 긍정적 영향을 미치는 것으로 나타났다.