• YAKHAK HOEJI
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• v.48 no.1
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• pp.1-5
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• 2004

The purpose of this study was to investigate the effect of coadministration and 3 days-pretreatmemt of niledipine (2, 10 mg/kg) on the pharmacokinetic parameters and bioavailability of paclitaxel (50 mg/kg) after oral administration in rats. Coadministration of nifedipine with paclitaxel did alter the $C_{max}$ (115${\pm}$29 ng/ml without nifedipine; 135${\pm}$35 ng/ml with nifedipine (10 mg/kg): p<0.05) and AUC (188${\pm}$459 ng/mlㆍhr with-out nifedipine; 2546${\pm}$642 ng/mlㆍhr with nifedipine; p<0.05). Three days treatment of nifedipine on the prior to paclitaxel administration increased the $t_{1/2}$ 〔9.90${\pm}$2.47 hr without nifedipine; 12.37${\pm}$3.12 hr with nifedipine (2 mg/kg): 12.83${\pm}$3.32 hr with nifedipine (10 mg/ml); p<0.05] and AUC [1833${\pm}$459 ng/mlㆍhr without nifedipine; 2663${\pm}$648 ng/mlㆍhr with nifedipine (2 mg/kg): 3006${\pm}$734 ng/mlㆍhr with nifedipine (10 mg/ml): p <0.05]. Drug interaction between nifedipine and paclitaxel decreased the elimination rate constant and increased the oral bioavailability of paclitaxel. On the basis of the results of this study, it might be considered that nifedip ine may inhibit cytochrome P450, which are engaged in paclitaxel metabolism, result in increased $t_{1/2}$ and AUC of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bio-availability wit/or without nifedipine.

• YAKHAK HOEJI
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• v.44 no.3
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• pp.245-250
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• 2000

Because nonsteroidal anti-inflammatory drugs are reported to cause fluid retention and hypertension by inhibition of prostaglandin synthesis, the effects of piroxicam on pharmacodynamics and pharmacokinetics of nifedipine were studied in male spontaneously hypertensive rats. They received nifedipine (0.5 mg/kg) alone or combined with piroxicam (5 mg/kg) intravenously. Plasma levels norepinephrine, an index of sympathetic stimulation, were measured prior to each treatment and 5 min after drug administration. Changes in blood pressure were examined serially and blood samples for analysis of nifedipine were also taken for 6 hr following drug administration. Plasma nifedipine concentration were assayed by HPLC and pharmacokinetic parameters were calculated. Blood pressure was reduced (p<0.01), but plasma norepinephrine level was increased (p<0.05) by nifedipine administration. Anti-hypertensive effect of nifedipine was potentiated (p<0.05) by piroxicam coadministration, but effect of nifedipine on plasma norepinephrine level was not affected. In case of rats received nifedipine and piroxicam, plasma nifedipine concentrations were higher (p<0.05) than those from rats received nifedipine alone at 2,3,4,5 and 6 hours following drug administration. The area under the plasma concentration vs. time curve was increased (p<0.05), while the elimination rate constant was decreased (p<0.01) by piroxicam coadministration. No significant differences were observed in the plasma clearance, apparent volume of distribution and elimination half-life. Thus, piroxicam not only potentiated antihypertensive effect of nifedipine, but also altered nifedipine pharmacokinetics in the rats. It is concluded that the potentiation of nifedipine antihypertensive effect might correlate with the increment of its plasma concentration by piroxicam coadministration.

• The Korean Journal of Physiology
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• v.24 no.1
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• pp.115-121
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• 1990

The interaction between a calcium channel blocker nifedipine and atrial natriuretic peptide (ANP) was examined in normotensive and renal hypertensive rats. The infusion of either ANP or nifedipine produced a significant decrease in mean arterial pressure (MAP). The combined infusion of ANP with nifedipine resulted in a greater fall of MAP than did the infusion of each drug alone. ANP significantly increased urinary volume and excretion of sodium, while nifedipine was without effects. The diuretic/natriuretic effects of ANP were potentiated by the combined infusion with nifedipine. The vasodepressor and renal effects of ANP or nifedipine were qualitatively similar between the normotensive and hypertensive rats. Nifedipine caused an upward and leftward shift of the ANP dose-relaxation curve of the phenylephrine-precontracted thoracic aortic rings isolated from the normotensive rats , suggesting that the vasodilation sensitivity to ANP is increased in the presence of nifedipine. These results indicate that nifedipine enhances the vasodepressor effect of ANP, the likely mechanisms being attributable to a contraction of effective intravascular volume as a consequence of potentiated renal excretion and a greater peripheral vasodilation.

• YAKHAK HOEJI
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• v.51 no.3
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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.

• Journal of Pharmaceutical Investigation
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• v.29 no.2
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• pp.93-98
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• 1999

Semi-solid poly(ortho esters) (POE) were prepared to provide bioerodible carriers for sustained drug delivery systems of nifedipine in the treatment of cardiovascular disease. As the POE has viscous behavior at room temperature, a significant advantage of this polymer is that it can be injected without any surgical intervention. The POE was synthesized by a transesterification reaction between 1,2,6-hexanetriol and trimethyl orthoacetate and the nifedipine release from POE was studied in vitro. The release rate of nifedipine decreased with increasing the amount of nifedipine and the diethanolamine dispersed in the polymer. But the excess amounts, above 3%, of diethanolamine retarded the release of nifedipine. In vivo biocompatibility studies were carried out in rats with nifedipine loaded POE. Histopathological analysis showed that nifedipine loaded POE implants were well-tolerated by rats when used subcutaneously. In case of the rats implanted POE containing diethanolamine, tissue necrosis and inflammation were occured. Pharmacokinetic studies of nifedipine loaded POE implants were carried out in rabbits. In all cases, plasma concentrations of nifedipine were maintained over 15 ng/ml for at least 360 hours and biological half $life(t_{1/2})$ and mean residence time(MRT) were increased by addition of diethanolamine.

• YAKHAK HOEJI
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• v.31 no.6
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• pp.376-393
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• 1987

This study was performed in order to investigate the effect of nifedipine, a vasodilating drug which acts through calcium antagonism, on renal function using mongrel dog. Nifedipine, when given interavenously in doses ranging from 1.5 to 5.0$\mu\textrm{g}$/kg, elicited diuresis along with less changes of glomerular filtration rate and significant increases of renal plasma flow, so that the filtration fraction(FF) decreased significantly, at the same time both osmolar and free water clearances increased, and amount of sodium, potassium and calcium excreted in urine increased significantly. Nifedipine, when infused into a renal artery in doses from 0.05 to 0.15$\mu\textrm{g}$/kg/min, exhibited identical responses to the actions of intraveneous nifedipine except significant increase of glomerular filtration rate and no change of FF, which was confined only to the infused kidney. The renal action of nifedipine into a renal artery were not influenced by renal denervation, decreased significantly by ouabain, Na$^+$-K$^+$-ATPase inhibitor, which was given into a renal artery. Nifedipine infused into a renal artery in dog pretreated with propranolol i.v. produced diuresis associated with the increase of electrolytes excretion by reduction of electrolyte reabsorption and with no changes of glomerular filtration rate and renal plasma flow. Thus, it is concluded that nifedipine infused into a renal aretery produces diuretic action along with both improvement of hemodynamics and inhibition of electrolytes reabsorption, which may be related to sympathetic $\beta$-receptor or Na$^+$-K$^+$-ATPase activity because the action of nifedipine in kidney is blocked by propranolol or ouabain.

• YAKHAK HOEJI
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• v.54 no.4
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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.

• Journal of Pharmaceutical Investigation
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• v.34 no.4
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• pp.283-288
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• 2004

The pharmacokinetics of nifedipine was studied after oral coadministration of nifedipine (5 mg/kg) with quercetin (1.5, 7.5, 15 and 30 mg/kg, respectively) and 0.5 h or 3days pretreatment with quercetin (1.5 and 7.5mg/kg) in rabbits. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the plasma concentration of nifedipine, but not significant in coadministraiton. The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of nifedipine pretreated with quercetin were increased significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) compared to the control. By coadministration of quercetin, only 7.5 mg/kg of quercetin increased plasma AUC and $C_{max}$ of nifedipine significantly (p<0.05) compared to the control. Plasma AUC of intravenous nifedipine (1 mg/kg) is $4235\;{\pm}\;1192\;ng/ml{\cdot}hr$. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the absolute bioavailability (AB%) of nifedipine to 23.9-29.2% compared to the control (17.8%). Coadministration of quercetin showed no significant effect on the AB% of nifedipine except for 7.5 mg/kg. It is suggested that quercetin alters disposition 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 chronically with quercetin in a clinical situation.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.282-282
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• 1996

The purpose of this study was to prepare the nifedipine dry elixir (NDE) and coated nifedipine dry elixir (CNDE) containing nifedipine ethanol solution for improving the dissolution rate and bioavailability of nifedipine. NDE containing nifedipine and ethanol in wall materials of dextrin was prepared using a spray-dryer and then NDE was coated with eudragit acrylic resin to make CNDE. Shape and size of the NDE and CNDE were monitored by scanning electron micrograph and laser particle size analyzer In vitro dissolution tests were performed in simulated gastric and intestinal fluid. Bioavailability of NDE and CNDE were compared with drug powder suspension and commercial soft capsule after oral administration of the preparations to rats. NDE and CNDE are spherical in shape. Cross-sectional view of dry elixirs indicates the large inter cavity containing ethanolic drug solution in shell. Geometric mean diameter of NDE and CNDE is about 6.64 and 8.70 $\mu\textrm{m}$, respectively. Drug dissolution rate within first 5 min from NDE increased dramatically irrespective of dissolution medium. However, CNDE showed a particularly retarded dissolution rate in pH 1.2 simulated gastric fluid compared with NDE. The bioavailability of nifedipine in the NDE was increased dramatically compared with drug powder suspension. CNDE reduced initial burst-out plasma peak compared with NDE. CNDE as a sustained release delivery system could reduce the initial burst-out plasma peak due to controlling the release rate of nifedipine from NDE and maintain the effective plasma level over a longer period within therapeutic window with enhanced bioavailability of nifedipine.

• Journal of Pharmaceutical Investigation
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• v.35 no.2
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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.