• 한국임상약학회지
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• 제19권1호
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• pp.32-36
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• 2009

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of nicardipine in rats. Pharmacokinetic parameters of nicardipine were determined after an oral administration of nicardipine (12 mg/kg) to rats coadministered with simvastatin (0.3 and 1.0 mg/kg). Compared with the control (given nicardipine alone), coadministration of simvastatin (1.0 mg/kg) significantly (p<0.05) increased the area under the plasma concentration (AUC) and peak plasma concentration ($C_{max}$) of nicardipine. The relative bioavailability (RB%) of nicardipine increased from 1.19- to 1.48-fold. However there were no significant changes in $t_{max}$, and $t_{1/2}$ of nicardipine. The enhanced oral bioavailability of nicardipine might be due to an inbition of cytochrom P450 3A mediated-metabolism of nicardipine in the intestine and in the liver by simvastatin. Based on these results, the concurrent use of simvastatin significantly enhanced the oral exposure of nicardipine in rats. The dosage regimen of nicardipine should be taken into consideration for potential drug interaction when combined with simvastatin in clinics.

• Archives of Pharmacal Research
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• 제28권3호
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• pp.319-324
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• 2005

The present study was designed to study the difference effects between nicardipine and its two enantiomers on thoracic artery of rabbit. A high-performance liquid chromatographic method was used to prepare the two enantiomers of nicardipine. The thoracic artery of rabbit was removed. The vessels were cut into 3 mm in width and 15 mm in length spiral strips and immersed into tissue baths. The concentration-response curves of nicardipine and its enantiomers were obtained by cumulative administration of the vasoconstrictors. Nicardipine and the enantiomers could shift the dose-response curves of NE, KCI or CaCl$_2$ to right in a nonparallel manner and decrease the maximum effective in a concentration-depended manner, respectively. The pD$_2$' value of R-(-)-nicardipine showed significantly effective than that of nicardipine and S-(+)-nicardipine (P<0.01). There was not obviouse difference between the pD$_2$' value of nicardipine and S-(+)-nicardipine (P>0.05). The results demonstrate that the stereoselective interaction between R-(-)-nicardipine and L-calcium channel receptor is more stronger than that of S-(+)-nicardipine.

• 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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• 제40권5호
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• pp.291-296
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• 2010

This study was to investigate the effect of baicalein, an antioxidant, on the bioavailability of nicardipine after orally or intravenously administered nicardipine in rats. Nicardipine was administered orally (12 mg/kg) or intravenously (4 mg/kg) with or without orally administered baicalein (0.4, 2 or 10 mg/kg) to rats. In the inhibitory effect of baicalein on CYP3A4 activity, baicalein inhibited CYP3A4 activity with $IC_{50}$ values of 9.2 ${\mu}M$. The cell-based P-gp activity test using rhodamine-123 also showed that baicalein (30-10 ${\mu}M$, p<0.01) significantly inhibited P-gp activity. Compared with the control group (given nicardipine alone), the area under the plasma concentration-time curve (AUC) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 25.9-60.0%, and the peak concentration ($C_{max}$) was significantly (10 mg/kg, P<0.01) increased by 40.0% in the presence of baicalein after orally administration of nicardipine. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.26- to 1.60-fold and the absolute bioavailability (A.B.) was significantly (2 mg/kg, P<0.05; 10 mg/kg, P<0.01) increased by 26.0-59.9%. Compared to the i.v. control, baicalein did not significantly change pharmacokinetic parameters of nicardipine in i.v. administration. Accordingly, the enhanced oral bioavailability of nicardipine might be mainly due to increased intestinal absorption caused by P-gp inhibition rather than to reduced elimination of nicardipine by baicalein. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the small intestine via the inhibition of P-gp and reduced first-pass metabolism of nicardipine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by baicalein. Based on these results, nicardipine dosage should be adjusted when given concomitantly with baicalein.

• 대한치과마취과학회지
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• 제10권2호
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• pp.166-171
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• 2010

Background: Controlled hypotension is used to reduce bleeding and improve surgical conditions during surgery. Nicardipine and remifentanil have been used to induce controlled hypotension in healthy patients. This study compared controllability of nicardipine and remifentanil on hemodynamic stability during controlled hypotension. Methods: Forty healthy patients scheduled for orthognathic two jaw surgery were randomly allocated to nicardipine (group N) and remifentanil (group R) group. After induction of anesthesia, group N (n = 20) was infused with nicardipine to induce hypotension and group R (n = 20) was infused with remifentanil. Mean arterial pressure (MAP) and heart rate (HR) were measured over 5 minute interval. Surgical field rating and blood loss were measured after surgery. Results: HR was lower in group R than group N. MAP was maintained at 50-60 mmHg during controlled hypotension but the fluctuation of blood pressure and HR were more frequent in group N than group R. There were no significant differences in the surgical field rating and blood loss between the groups. Conclusions: Nicardipine and remifentanil enabled controlled hypotension and provided good surgical conditions, but the fluctuation of hemodynamic parameters was more frequent in nicardipine group.

• Biomolecules & Therapeutics
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• 제18권4호
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• pp.448-453
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• 2010

Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG $K^+$ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an $IC_{50}$ of 0.43 ${\mu}M$. On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.

• Journal of Chest Surgery
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• 제35권4호
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• pp.267-273
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• 2002

배경: 저자들은 한국인에 있어서의 급성대동맥박리에 대한 nicardipine의 혈압강하요법에 대한 임상적 유용성을 검토하고자 국내 제4상 임상시험을 실시하였다. 대상 및 방법: 31명의 대동맥 질환 환자에서 시험약의 투여 전후의 수축기 및 이완기 혈압, 심박수 등을 시간변화에 따라 비교 관찰하였다. 시험약식 투여기간은 원칙적으로 3일 이상 14일 이하로 하였으며, 투여 3일째의 평균혈압강하도를 평가하였다. 시험약 사용전 다른 강압제를 사용하고 있었던 경우는 기존 사용약제의 용량을 줄이면서 시험약으로 대체하여 결국 기존 사용약제를 사용하지 않는 것을 원칙으로 하였다. 결과: 연구의 대상이 된 환자는 급성 대동맥 박리가 28명, 대동맥궁류 파열이 2명, 외상성 대동맥 파열이 1명이었다. 연령은 53.9$\pm$14.9(29~89)세였고, 남자가 21명 (67.7%)이었다. 대동맥질환에 기인한 합병증은 대동맥판 폐쇄부전이 7례, 혈성심낭 6례, 급성 신부전 1례, 하지마비 1례, 하지허혈 1례 등이었다. 목표혈압 도달은 15분이내가 16례로 가장 많았고, 15분이상 30분이내가 10명, 30분이상 45분이내가 3명, 45분이상 60분 이내에 도달한 경우가 2명이었다. 관찰기 혈압은 수축기혈압, 이완기혈안, 평균혈압이 각각 147$\pm$23mmHg, 82.3$\pm$18.6mmHg, 104$\pm$18mmHg이었고, 3일째 측정하였을 때 119$\pm$12mrnHg, 69$\pm$grnmHg, 86$\pm$BmmHg로 의미있게 감소하였음을 확인하였다. Nicardipine 투여 종료 시에측정한 수축기 혈압, 이완기혈압, 평균혈압은 각각 119$\pm$ 15mmHg, 70$\pm$ 14mmHg, 86$\pm$ 13mmHg로 3일째 측정한 혈압과 비교하였을 때 의미있는 상승 혹은 하강현상은 관찰되지 않았고 비교적 혈압 하강 상태가 잘 유지되고 있음을 알 수 있었다. 지속적 정맥 투여 중 부작용은 뚜렷하게 관찰할 수 없었다. 결론: 대동맥 박리에 동반된 고혈압에서 nicardipine을 사용하여 만족할만한 혈압하강 효과를 얻었으며, 뚜렷한 부작용이 없이 안전하게 사용할 수 있다는 결론을 내렸다.

• 한국임상약학회:학술대회논문집
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• 한국임상약학회 2007년도 추계학술대회
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• pp.166-166
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• 2007

• Journal of Pharmaceutical Investigation
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• 제35권6호
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• pp.461-465
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• 2005

A simple HPLC method with ultraviolet detection of nicardipine in human plasma was developed and validated. After drug extraction with solid phase extraction (SPE) method, chromatographic separation of nicardipine in plasma was achieved at $30^{\circ}C$ with a $C_{18}$ column and acetonitrile-0.02% phosphate buffer mixture (with 0.02% triethylamine, final pH 7.0), as mobile phase. Quantitative determination was performed by ultraviolet detection at 254 nm. The method was specific and validated with a limit of quantification of 5 ng/mL. The intra- and inter-day precision and accuracy were acceptable for all quality control samples including the lower limit of quantification. The applicability of the method was demonstrated by analysis of plasma after oral administration of a single 40 mg dose to 8 healthy subjects. From the plasma nicardipine concentration versus time curves, the mean $AUC_{t}$, was $134.04{\pm}59.72\;ng\;hr/mL$ and $C_{max}$ of $108.65{\pm}69.17\;ng/mL$ reached 1.5 hr after administration. The mean biological half-life of nicardipine was $3.93{\pm}0.82\;hr$. Based on the results, this simple and validated assay method could readily be used in any pharmacokinetic or bioequivalence studies using human.

• Biomolecules & Therapeutics
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• 제6권4호
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• pp.389-394
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• 1998

Cyclosporine (CsA) is a major immunosuppressive drug used widely to prevent organ allograft rejection. fits potential organotoxicity by prolonged use is known to cause both direct tissue damage and indirect pharmacokinetic interactions with other drugs. This study was performed to determine the effect of nicardipine (NCP) on the pharmacokinetic parameters of CsA in Sprague-Dawley rats. Each rat was administered with CsA in saline-treated group or in NCP-treated group which was pretreated with NCP (5 mg/kg/12 hours, i.p.) for 6 days. The plasma CsA concentration were analyzed by reversed HPLC: UV system at 0.5, 1, 2, 4, 6, and 8 hours after bolus injection of CsA (10 mg/kg). Pharmacokinetic parameters (mean$\pm$ SD, n=7) such as initial plasma concentration (C(0)), mean residence time (MRT), steady-state volume of distribution (Vdss), terminal half-life (t$\frac{1}{2}$($\beta$)) and plasma clearance (CLp) of CsA in each groups (saline-group vs NCP-group) were determined as follows: C(0) (5.66$\pm$ 1.98 vs 17.98$\pm$2.36, p<0.01); Vdss (2.68$\pm$ 1.6 vs 0.94 $\pm$ 0.25, p<0.01); CLp (0.53 $\pm$0.18 vs 0.21 $\pm$0.06, p<0.01). Therefore, Our results indicate that nicardipine significantly affects the pharmacokinetic parameters of cyclosporme, especially C(0), Vdss, and CLp in NCP-treated group. We suggest that the significant pharmacokinetic interaction between cyclosporine and nicardipine should be considered and cyclosporine level should be closely monitored and dosage reduction made as necessary in clinical situation that was coadministered with CsA and NCP.