• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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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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• v.28 no.3
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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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• v.18 no.2
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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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• v.40 no.5
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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.

• Journal of The Korean Dental Society of Anesthesiology
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• v.10 no.2
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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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• v.18 no.4
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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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• v.35 no.4
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• pp.267-273
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• 2002

Background: We performed a phase IV clinical trial to examine the usefulness of a continuous infusion of nicardipine hydrochloride to control hypertension in patients with acute aortic dissection. material and Method: Systolic/diastolic blood pressure, and heart rate were monitored before and after the intravenous administration of nicardipine in 31 patients with aortic diseases. The period of nicardipine administration in each patient was from 3 to 14 days. Efficacy was evaluated by determining the average amount of blood pressure reduction on the 3rd day of drug administration. The dosage of another antihypertensive agent was slowly tapered down, and ultimately replaced by the test drug. Result: 28 patients were diagnosed as acute aortic dissection, 2 patients as rupture of the aortic arch aneurysm, and 1 patient as traumatic aortic rupture. Mean age was 53.9 $\pm$ 14.9(29~89) years, and 21 patients(67.7%) were male. 14 patients(32.3%) had complications associated with underlying aortic disease: aortic insufficiency in 7, hemopericardium in 6, acute renal failure in 1, paraplegia in 1, lower extremity ischemia in 1, and hemothorax in 1. The time needed to reach the target blood pressure was within 15 minutes in 16, from 15 to 30 minutes in 10, from 30 to 45 minutes in 3 and from 45 to 60 minutes in 2, and their baseline average systolic, diastolic, and mean arterial blood pressures(mmHg) were 147$\pm$23, 82.3$\pm$ 18.6, and 104 $\pm$ 18, respectively. Average systolic, diastolic, and mean arterial blood pressures(mmHg) on the third day of nicardipine infusion were 119$\pm$ 12, 69$\pm$9, and 86$\pm$8, and they all showed statistically significant decrease(p<0.05). The average systolic, diastolic, and mean arterial blood pressure(mmHg) after the discontinuation of the nicardipine infusion were 119 $\pm$ 15, 71 $\pm$ 14, and 86$\pm$ 13, respectively. No significant difference was observed between the average pressures measured on the third day and those measured after the discontinuation of the nicardipine infusion, and no definite side effects were observed during the study period. Conclusion: Nicardipine hydrochloride was both effective and safe at controlling blood pressure in patients with acute aortic dissection.

• 한국임상약학회:학술대회논문집
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• 2007.12a
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• pp.166-166
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• 2007

• Journal of Pharmaceutical Investigation
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• v.35 no.6
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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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• v.6 no.4
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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.