• 셀메드
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• 제2권2호
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• pp.18.1-18.16
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• 2012

An oncology-specific database called OncoRx (http://bit.ly/cancerRx) was previously set up in cyberspace to aid clinicians in identifying interactions of anticancer drugs (ACDs) and chemotherapy regimens with traditional Chinese medicines (TCMs) and complementary and alternative medicines (CAMs). Since then, users have requested the drug-CAM interactions (DCIs) of 5 specific CAMs (cranberry, melatonin, co-enzyme Q10, huachansu, reishi mushroom) to be updated in the database. Pharmacokinetic properties (metabolism, enzyme induction/inhibition, elimination), TCM properties and DCIs of each CAM were collated with 117 ACDs using 9 hardcopy compendia and online databases as resources. Additionally, individual ACDs and CAMs were used as keywords for PubMed searches in combination with the terms 'anticancer drugs', 'drug interactions', 'herb-drug/drug-herb interactions', 'pharmacokinetic interactions' and 'pharmacodynamic interactions'. DCI parameters consisted of interaction effects, evidence summaries, proposed management plans and alternative non-interacting CAMs, together with relevant citations and update dates of the DCIs. OncoRx is also used as a case to introduce the "Four Pharmaco-cybernetic Maxims" of quality, quantity, relationship and manner to developers of digital healthcare tools. Its role in Hayne's "5S" hierarchy of research evidence is also presented. OncoRx is meant to complement existing DCI resources for clinicians and alternative medicine practitioners as an additional drug information resource that provides evidence-based DCI information for ACD-CAM interactions.

• Mass Spectrometry Letters
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• 제11권1호
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• pp.10-14
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• 2020

Riboflavin is a water-soluble vitamin, which serves as a precursor to flavin mononucleotide and flavin adenine dinucleotide. This study aimed to develop a simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for the quantification of riboflavin in the Beagle dog plasma. This method utilized simple protein precipitation with acetonitrile and ¹³C₄, ¹⁵N₂-riboflavin was used as an internal standard (IS). For chromatographic separation, a hydrophilic interaction liquid chromatography (HILIC) column was used with gradient elution. The mobile phase consisted of 0.1% (v/v) aqueous formic acid with 10 mM ammonium formate and acetonitrile with 0.1% (v/v) formic acid. Since riboflavin is an endogenous compound, 4% bovine serum albumin in phosphate buffered saline was used as a surrogate matrix to prepare the calibration curve. The quantification limit for riboflavin in the Beagle dog plasma was 5 ng/mL. The method was fully validated for its specificity, sensitivity, accuracy and precision, recovery, and stability according to the US FDA guidance. The developed LC-MS/MS method may be useful for the in vivo pharmacokinetic studies of riboflavin.

• Toxicological Research
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• 제33권1호
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• pp.25-30
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• 2017

Saccharin, the first artificial sweetener, was discovered in 1879 that do not have any calories and is approximately 200~700 times sweeter than sugar. Saccharin was the most common domestically produced sweetener in Korea in 2010, and it has been used as an alternative to sugar in many products. The interaction between artificial sweeteners and drugs may affect the drug metabolism in patients with diabetes, cancer, and liver damage, this interaction has not been clarified thus far. Here, we examined the effects of the potential saccharin-drug interaction on the activities of 5 cytochrome P450 (CYPs) in male ICR mice; further, we examined the effects of saccharin (4,000 mg/kg) on the pharmacokinetics of bupropion after pretreatment of mice with saccharin for 7 days and after concomitant administration of bupropion and saccharin. Our results showed saccharin did not have a significant effect on the 5 CYPs in the S9 fractions obtained from the liver of mice. In addition, we observed no differences in the pharmacokinetic parameters of bupropion between the control group and the groups pretreated with saccharin and that receiving concomitant administration of saccharin. Thus, our results showed that saccharin is safe and the risk of saccharin-drug interaction is very low.

• Journal of Pharmaceutical Investigation
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• 제33권3호
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• pp.223-227
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• 2003

The purpose of this study was to investigate the effect of ketoconazole (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with ketoconazole was significantly (p<0.05) increased from 8 hr to 24 hr compared to that of control. Area under the plasma concentration-time curve (AUC) of paclitaxel with ketoconazole was significantly (coadministration p<0.05, pretreatment p<0.0l) higher than that of control. Peak concentration $(C_{max})$ of paclitaxel pretreated with ketoconazole were significantly (p<0.05) increased compared to that of control. Time to peak concentation $(T_{max})$ of paclitaxel pretreated with ketoconazole were significantly (p<0.05) shorter than that of control. Half-life at elimination phase $(t_{1/2{\beta}})$ of paclitaxel pretreated with ketoconazole was significantly (p<0.05) prolonged compared to that of control. Based on these results, it might be due to both inhibition of the enzyme cytochrome P450 and p-glycoprotein, which engaged in paclitaxel absorption and metabolism in liver and gastrointestinal mucosa.

• 약학회지
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• 제49권5호
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• pp.380-385
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• 2005

The aim of this study is to investigate the effects of verapamil on the pharmacokinetics of tamoxifen following oral administration of tamoxifen with verapamil to rats. Tamoxifen (10 mg/kg) was administered orally in the presence or absence of verapamil (1, 3 or 6 mg/kg). Compared to the control group (given tamoxifen alone), the presence of verapamil significantly (p<0.05 by 1 mg/kg, p<0.01 by 3 and 6 mg/kg) increased the areas under the plasma concentration-time curve (AUC) and the peak concentrations ($C_{max}$) of tamoxifen. Consequently, the relative bioavailability ($RB\%$) of tamoxifen with verapamil was 1.6-2.1 fold higher than that of the control. But the time to reach peak concentration ($T_{max}$) and the terminal half-life ($t_{1/2}$) of tamoxifen were not altered significantly in the presence of verapamil. The increased AUC and $C_{max}$ of tamox­ifen in the presence of verapamil might be associated with the inhibition by verapamil of the P-glycoprotein and the first­pass metabolizing enzyme CYP3A4 in small intestinal mucosa. The drug interaction should be taken into consideration when tamoxifen is used to the patient with verapamil in the clinical setting.

• 약학회지
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• 제47권2호
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• pp.98-103
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• 2003

The purpose of this study was to investigate the effect of flavone (20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (40 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel in combination with flavone was increased significantly (coadministration p＜0.05, pretreatment p＜0.0l) compared to that of control. Area under the plasma concentration-time curve (AVC) of paclitaxel with flavone was significantly (coadministration p＜0.05, pretreatment p＜0.0l) higher than that of control. Peak concentration (Cmax) of paclitaxel with flavone were significantly increased (coadministration p＜0.05, pretreatment p＜0.01) compared to that of control. Time to peak concentration (Tmax) of paclitaxel with flavone decreased significantly (p＜0.05) than that of control. The total body clearance (CLt) and elimination rate constant ($\beta$) of paclitaxel with flavone were significantly reduced (p＜0.05) compared to those of control. Half-life (t$_{1}$2/) of paclitaxel with flavone was significantly prolonged (p＜0.05) compared to that of control. Based on these results, it might be concluded that flavone may enhance bioavailability of paclitaxel through the inhibition of cytochrome P450 and P-glycoprotein, which are engaged in paclitaxel absorption and metabolism in liver and gastrogintestinal mucosa, respectively.

• Mass Spectrometry Letters
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• 제8권4호
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• pp.98-104
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• 2017

Ginseng (Panax ginseng Meyer) is a well-known health functional food used as a traditional herbal drug in Asian countries owing to its diverse pharmacological effects. Herb-drug interactions may cause unexpected side effects of co-administered drugs by the alteration of pharmacokinetics through effects on cytochrome P450 activity. In this study, we investigated the herb-drug interactions between Korean red ginseng extract (KRG) and five CYP-specific probes in mice. The pharmacokinetics of KRG extract induced-drug interactions were studied by cassette dosing of five CYP substrates for CYP1A, 2B, 2C, 2D, and 3A and the LC-MS/MS analysis of the blood concentration of metabolites of each of the five probes. The linearity, precision, and accuracy of the quantification method of the five metabolites were successfully confirmed. The plasma concentrations of five metabolites after co-administration of different doses of the KRG extract (0, 0.5, 1, and 2 g/kg) were quantified by LC-MS/MS and dose-dependent pharmacokinetic parameters were determined. The pharmacokinetic parameters of the five metabolites were not significantly altered by the dose of the KRG extract. In conclusion, the single co-administration of KRG extract up to 2 g/kg in vivo did not cause any significant herb-drug interactions linked to the modulation of CYP activity.

• Biomolecules & Therapeutics
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• 제18권3호
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• pp.343-349
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• 2010

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $25.2\;{\mu}M$. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration ($C_{max}$) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• 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.