• 대한핵의학회:학술대회논문집
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• 2001.05a
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• pp.66-75
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• 2001

Although diverse mechanisms are involved in multidrug resistance for chemotherapeutic drugs, the development of cellular P-glycoprotein(Pgp) and multidrug-resistance associated protein (MRP) are important factors in the chemotherapy failure to cancer. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However these methods do not yield information about dynamic function of Pgp and MRP un vivo. Single photon emission tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transport. $^{99m}Tc$-sestaMIBl and other $^{99m}Tc$-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with $^{11}C$ have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-$[^{11}C]$acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. Results obtained from recent publications are reviewed to confirm the feasibility of using SPECT and PET to study the functionality of MDR transporters in vivo.

• Clinical and Experimental Pediatrics
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• v.51 no.10
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• pp.1031-1037
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• 2008

Macrolide antimicrobial agents including erythromycin, roxithromycin, clarithromycin, and azithromycin are commonly used in the treatment of respiratory tract infections in children. Newer macrolides that have structural modifications of older drug erythromycin show improved change in the spectrum of activity, dosing, and administration. However, recent studies reported that increasing use of macrolide antibiotics is the main force driving the development of macrolide resistance in streptococci. In particular, azithromycin use is more likely to select for macrolide resistance with Streptococcus pneumoniae than is clarithromycin use, a possible reflection of its much longer half life. Recently, erythromycin resistance rates of S. pneumoniae and Streptococcus pyogenes are rapidly increasing in Korea. Two main mechanisms of acquired macrolide resistance have been described, altered binding site on the bacterial ribosome encoded by the ermB gene and active macrolide efflux pump encoded by the mef gene. Relationship between the susceptibility of S. pneumoniae and the response to macrolides has been shown in studies of acute otitis media, but less clear in cases of pneumonia. This article reviews the spectrum of activity, pharmacokinetic properties, mechanisms of action and resistance, and clinical implication of resistance on the treatment of respiratory tract infections in children.

• 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.

• Journal of Pharmaceutical Investigation
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• v.34 no.1
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• pp.15-21
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• 2004

The pharmacokinetics of orally administered verapamil (10 mg/kg) was studied in six rabbits after 20 min pretreatment with quercetin ad coadministration of quercetin (2.0 mg/kg, 1 mg/g and 20 mg/kg, respectively). Pretreatment with quercetin significantly (p < 0.01, p < 0.05) increased the plasma concentration of verapamil. However, coadministration of quercetin showed no significantly effect on the pharmacokinetic parameters of verapamil. The elimination rate constant $(K_{el})$ of verapamil pretreated with quercetin (1 mg/kg and 20 mg/kg) was significantly (p < 0.05) reduced compared with control. The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of verapamil pretreated with quercetin (2.0 mg/kg, 10 mg/kg and 20 mg/kg) were increased significantly (p < 0.01, p < 0.05) compared with control. Pretreatment with quercetin (2.0 mg/kg, 10 mg/kg and 20 mg/kg) significantly (p < 0.01, p < 0.05) increased the relative bioavailability of verapamil to 159 - 219%. These results suggest that quercetin alters disposition of verapamil by inhibition of P-glycoprotein efflux pump and its first-pass metabolism. The dosage of verapamil should be adjusted when it is administered chronically with quercetin in a clinical situation.

• YAKHAK HOEJI
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• v.48 no.4
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• pp.226-230
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• 2004

The pharmacokinetics of orally administered paclitlxel (50 mg/kg) was studied in six rabbits after 1hr pretreatment (2.0 mg/kg and 10 mg/kg) of tetramethoxyflavone or coadministration of (2.0 mg/kg, 10 mg/kg and 20 mg/kg) tetramethoxyflavone. The area under the plasma concentration-tine curve (AUC) and plasma concentration of paclitaxe1 coadministered with tetramethoxyflavone (10 mglkg) were increased significantly (p<0.05) compared with control. However, coadministration of tetramethoxyflavone (2 and 20 mg/kg) showed no significant effect on the pharmacokinetic parameters of paclitaxel. Pretreatment with tetramethoxyflavone significantly (p<0.05) increased the plasma concentration of paclitaxel. The area under the plasma concentration-time curve (AUC) and the peak concentration (C$_{max}$) of paclitaxel pretreated with tetramethoxyflavone were increased significantly (p<0.01, p<0.05) compared with control. The terminal half. life of paclitaxel pretreated with tetramethoxyflavone (2 mg/kg and 10 mg/kg) was significantly (p<0.05) prolonged compared with control. Pretreatment with tetramethoxyflavone (2.0 mg/kg, 10 mg/kg) significantly (p<0.01, p<0.05) increased the absolute bioavailability of paclitaxel compared with the control (154∼179%). On the basis of the results, it might be considered that tetramethoxyflavone may inhibit cytochrome P450 or P-glycoprotein efflux pump which are engaged in paclitaxel metabolism, result in increased AUC and t$_{1}$2/ of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone. P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone.

• Korean Journal of Clinical Pharmacy
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• v.17 no.1
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• pp.33-37
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• 2007

The purpose of this study was to investigate the effect of atorvastatin on the pharmacokinetics of diltiazem (15 mg/kg) after oral administration of diltiazem with or without atorvastatin (0.5, 1.5 and 3.0 mg/kg) in rats. Coadministration of atorvastatin increased significantly (p<0.05, 3.0 mg/kg) the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of diltiazem compared to the control group. The total plasma clearance (CL/F) of diltiazem was decreased significantly (p<0.05, 3.0 mg/kg) compared to the control group. The relative bioavailability (RB%) of diltiazem was increased from 1.14- to 1.49-fold. Coadministration of atorvastatin did not significantly change the elimination rate constant $(K_{el})$, terminal half-life $(T_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of diltiazem. 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.

• Korean Journal of Clinical Pharmacy
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• v.16 no.1
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• pp.57-62
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• 2006

The purpose of this study was to investigate the effect of naringenin, one of flavonoids, on the pharmacokinetics and bioavailability of diltiazem (15 mg/kg) after oral administration of diltiazem with or without naringenin (2.0, 10 and 20 mg/kg) in rabbits. Coadministration of naringenin increased the absorption rate constant $(K_a)$, the area under the plasma concentration-time curve (AUC) and peak concentration $(C_{max})$ of diltiazem compared to the control group, but only significantly (p<0.05) by 10mg/kg of naringenin coadministration. The absolute bioavailability (AB%) of diltiazem by coadministration ranges from 7.8% to 10.3%, increased more than control (7.2%), and relative bioavailability (RB%) of diltiazem is increased from 1.08- to 1.43-fold. Coadministration caused on significant changes in the terminal half-lives $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of diltiazem. On the other hand, coadministration of naringenin increased the AUC desacetyldiltiazem, significantly at the dose of 10mg/kg. But the metabolite ratio (MR) was decreased, significantly at 10mg/kg of naringenin. Based on these results, we can make a conclusion that the increased bioavailability and the significant changes of these pharmacokinetic parameters might be due to naringenin, which possess the potency to inhibit the metabolizing enzyme (CYP3A4) in the liver and intestinal mucosa, and also inhibit the P-glycoprotein efflux pump in the intestinal mucosa.

• Journal of Pharmaceutical Investigation
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• v.37 no.5
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• pp.311-314
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• 2007

Paclitaxel (PTX) is an antineoplastic agent approved for the treatment of ovarian and breast carcinomas. However, the use of paclitaxel as an anticancer drug is limited by its extremely poor water solubility (below $0.3\;{\mu}g/mL$). Furthermore, it has very low bioavailability when administered orally because paclitaxel is a substrate of P-glycoprotein (P-gp) efflux pump. In this study, buccal delivery of PTX was investigated as one of the alternatives for PTX delivery. Ethanol and glyceryl monooleate (GMO) were selected as permeation enhancing agents to increase solubility and permeation across buccal mucosa of PTX. At the different concentrations of ethanol solution ($30{\sim}70\;w/w\;%$), PTX permeation was studied, followed effects of GMO in the concentration range of $2.5{\sim}25%$ with ethanol vesicle. The transbuccal ability of PTX was evaluated in vitro using Franz diffusion cells mounted with rabbit buccal mucosa. As a result, incorporation of PTX into ethanol vesicle with GMO significantly enhanced the PTX permeation in rabbit buccal mucosa. Particularly, the mixtures of ethanol:water:GMO at the ratio of 50:47.5:2.5 showed the most excellent enhancing ability. The results showed a promising possibility for buccal delivery of PTX.

• 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.

• YAKHAK HOEJI
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• v.54 no.5
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• pp.370-376
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• 2010

The aim of this study is to investigate the effect of apigenin on the pharmacokinetics of tamoxifen in rats. Tamoxifen was administered orally (10 mg/kg) or intravenously (2 mg/kg) without or with oral administration of apigenin (0.4, 2.0 or 8.0 mg/kg) to rats. The effect of apigenin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Apigenin inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The plasma concentrations of tamoxifen were increased significantly by apigenin compared to control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations ($IC_{max}$) of tamoxifen with apigenin were significantly higher than those of the control group. Consequently, the relative bioavailability (RB%) of tamoxifen with apigenin was 2-3-fold higher than the control, and absolute bioavailability (AB%) of tamoxifen were significantly higher (p<0.05 with co-administration, p<0.01 with pretreatment) than those of the control. The increased bioavailability of tamoxifen in rats with apigenin might be associated with the inhibition of an efflux pump P-glycoprotein and CYP3A4 by apigenin. From these results, dosage regimen of tamoxifen may be need to adjust when concomitantly administered with apigenin.