• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.301-307
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• 2011

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $17.1{\mu}M$. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve ($AUC_{0-\infty}$) and the peak plasma concentration ($C_{max}$) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

• Asian Pacific Journal of Cancer Prevention
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• 제16권8호
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• pp.3447-3450
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• 2015

Objective: To explore the sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 (COX-2) expression in cancer tissue. Materials and Methods: Forty-three elderly patients with gastric cancer (observation group) and 31 young patients with gastrointestinal tumors (control group) who were all diagnosed by pathology and underwent surgery in the 89th Hospital of Chinese People's Liberation Army were selected. Drug sensitivity testing of tumor cells in primary culture was carried out in both groups using a methyl thiazolyl tetrazolium (MTT) method, and the expression of COX-2 and the factors related to multi-drug resistance (MDR) in cancer tissue were assessed by immunohistochemistry. Results: The inhibition rates (IR) of vincristine (VCR), 5-fluorouracil (5-FU), oxaliplatin (L-OHP), mitomycin (MMC) and epirubicin (eADM) on tumor cells in the observation group were dramatically lower than in the control group, with statistical significance (P<0.05 or P<0.01). The positive rates of COX-2, glutathione s-transferase-${\pi}$ (GST-${\pi}$) and P glycoprotein (P-gp) expression in cancer tissue in the observation group were all higher than in control group (P<0.05), while that of DNA topoisomerase $II{\alpha}$ ($TopoII{\alpha}$) expression lower than in the control group (P<0.01). In the observation group, COX-2 expression in cancer tissue had a significantly-positive correlation with GST-${\pi}$ and P-gp (r=0.855, P=0.000; r=0.240, P=0.026), but a negative correlation with $TopoII{\alpha}$ (r=-0.328, P=0.002). In the control group, COX-2 expression in cancer tissue was only correlated with P-gp positively (r=0.320, P=0.011). Bivariate correlation analysis displayed that COX-2 expression in cancer tissue in the observation group had a significantly-negative correlation with the IRs of 5-FU, L-OHP, paclitaxel (PTX) and eADM in tumor cells (r=-0.723, P=0.000; r=-0.570, P=0.000; r=-0.919, P=0.000; r=-0.781, P=0.000), but with hydroxycamptothecine (HCPT), VCR and 5-FU in the control group (r=-0.915, P=0.000; r=-0.890, P=0.000; r=-0.949, P=0.000). Conclusions: Gastric cancer cells in elderly patients feature stronger MDR, which may be related to high COX-2 expression.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.212-213
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• 2002

Using the isolated perfused rat heart this study investigated 1) the cardiac uptake of idarubicin (IDA), 2) the role of P-glycoprotein (P-gp) in the uptake process, 3) the formation of IDOL from IDA in the heart, and 4) the effect of P-gp inhibitors (verapamil, amiodarone, PSC 833), doxorubicin, hypothermia, xanthine derivatives (caffeine, theophylline) and metabolism inhibitors (rutin, phenobarbital) on the pharmacokinetics and pharmacodynamics of IDA using a mathematical modeling approach. A minimal model was constructed; the differential equations were numerically solved and fitted to the data using the ADAPT II-software package using maximum likelihood estimation assuming that the measurement error has a standard deviation which is a linear function of the measured quantity［1］. (omitted)

• Bulletin of the Korean Chemical Society
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• 제32권12호
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• pp.4444-4446
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• 2011

• 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.

• 한국임상약학회지
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• 제20권1호
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• pp.25-29
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• 2010

The purpose of this study was to investigate the effect of atorvastatin on the pharmacokinetics of nifedipine (6 mg/kg) after oral administration of nifedipine with or without atorvastatin (0.5 and 2.0 mg/kg) in rats, and also was to evaluate to the effect of atorvastatin on the CYP3A4 activity. The 50% inhibiting concentration ($IC_{50}$) values of atorvastatin on CYP3A4 activity is 46.1 ${\mu}M$. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner. Coadministration of atorvastatin increased significantly (p<0.05, 2.0 mg/kg) the plasma concentration-time curve (AUC) and the peak concentration ($C_{max}$) of nifedipine compared to the control group. The relative bioavailability (RB%) of nifedipine was increased from 1.15- to 1.37-fold. Coadministration of atorvastatin did not significantly change the terminal half-life ($T_{1/2}$) and the time to reach the peak concentration ($T_{max}$) of nifedipine. Based on these results, we can make a conclusion that the significant changes of these pharmacokinetic parameters might be due to atorvastatin, which possesses the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein (P-gp) efflux pump in the intestinal mucosa. It might be suggested that atorvastatin altered disposition of nifedipine by inhibition of both the first-pass metabolism and P-glycoprotein efflux pump in the small intestine of rats. In conclusion, the presence of atorvastatin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of atorvastatin with nifedipine should require close monitoring for potential drug interation.

• 약학회지
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• 제51권3호
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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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• 제41권3호
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• pp.153-159
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• 2011

This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol after oral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 5.2 ${\mu}M$ and 85.4 ${\mu}M$, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under the plasma concentration-time curve was significantly increased by 36.3-57.1%, and the peak concentration was significantly increased by 51.1-88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bio-availability of carvedilol was increased by 1.13- to 1.57-fold and the absolute bioavailability was significantly increased by 38.6-59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bio-availability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux of carvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin.

• Biomolecules & Therapeutics
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• 제19권4호
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• pp.498-503
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• 2011

The purpose of this study was to investigate the effects of nisoldipine on the pharmacokinetics of repaglinide in rats. The effect of nisoldipine on cytochrome P450 (CYP) 3A4 activity and P-glycoprotein (P-gp) were evaluated. The pharmacokinetic parameters of repaglinide were also determined in rats after oral (0.5 $mg{\cdot}kg^{-1}$) and intravenous (0.2 $mg{\cdot}kg^{-1}$) administration of repaglinide to rats without or with nisoldipine (0.3 and 1.0 $mg{\cdot}kg^{-1}$). Nisoldipine inhibited CYP3A4 enzyme activity with a 50% inhibition concentration of 5.5 ${\mu}M$. In addition, nisoldipine significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, nisoldipine significantly increased the $AUC_{0-{\infty}}$ and the $C_{max}$ of repaglinide by 46.9% and 24.9%, respectively. Nisoldipine also increased the absolute bioavailability (A.B.) of repaglinide by 47.0% compared to the oral control group. Moreover, the relative bioavailability (R.B.) of repaglinide was 1.16- to 1.47-fold greater than that of the control group. Nisoldipine enhanced the oral bioavailability of repaglinide, which may be attributable to the inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and to inhibition of P-gp in the small intestine rather than to reduction of renal elimination of repaglinide by nisoldipine. The increase in the oral bioavailability of repaglinide should be taken into consideration of potential drug interactions when co-administering repaglinide and nisoldipine.

• Journal of Pharmaceutical Investigation
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• 제38권5호
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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.