• Journal of Environmental Health Sciences
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• v.40 no.5
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• pp.407-412
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• 2014

Objectives: The internal dose of ethyl parabens is important in order to evaluate the risk of this chemical. However, there are little PK model data for parabens to apply this. This experiment attempted PK modeling to ascertain PK values. Methods: Twenty mg/kg ethyl paraben was administered orally to Sprague-Dawley rats at the same point in time. The rats were sacrificed at times 0, 15, 30 and minutes, and 1, 2, 4, 8, 12, 24 hours after oral gavage. Blood and urine were collected and pretreated for analysis. Accuracy, precision and LOD (limit of detection) were calculated for this analysis. Ethyl paraben, detected by HPLC-MS, was applied to PK modeling using Berkeley Madonna. Results: This study showed 100.1-103.7% accuracy, 1.4-3.7% precision and a 1.0 ng/mL limit of detection. Orally administered ethyl paraben reached maximum concentration after 30 minutes of dosing in serum and urine of rats. The concentrations were 2,354 ng/mL in serum and 386,000 ng/mL in urine samples. These peak concentrations were excreted after one hour of intubation over 12 hours. For the pharmacokinetic parameters of ethyl paraben revealed using Berkeley Madonna, the absorption rate was 5.539/hour, the excretion rate was 0.048/hour, the half-life was 14.441 hours and AUC was 481,186 ng hour/mL. Conclusion: Orally administered ethyl paraben was absorbed rapidly in rats and excreted in urine. This chemical, ethyl paraben, accumulated in the body but was excreted over 12 hours after dosing.

• Journal of Pharmaceutical Investigation
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• v.36 no.6
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• pp.377-383
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• 2006

The purpose of the present study was to examine the pharmacokinetic characteristics of arsenic hexaoxide($As_4O_6$), a novel anticancer compound, after i.v. bolus and oral administration in rats. We developed an ICP-Mass based method to analyze arsenic hexaoxide levels in plasma, bile, urine, feces, and tissue and validated the method. Arsenic hexaoxide rapidly disappeared from the plasma by 10 min($\alpha$ phase) after i.v. administration, which was followed by the late disappearance in the $\beta$ phase. The mean plasma half-lives($t_{1/2}$) of arsenic hexaoxide at the a and $\beta$ phase when administered at a dose of 5 mg/kg were 1.57 and 29.8 min, respectively. The maximum plasma concentration($C_{max}$) was 230 ng/mL, after oral administration of arsenic hexaoxide at a dose of 50 mg/kg. The bioavailability, which was calculated from the dose-adjusted ratio, of the oral administered arsenic hexaoxide was 1.61%. Of the various tissues tested, arsenic hexaoxide was mainly distributed in the spleen, lung, liver and kidney after oral administration. Arsenic hexaoxide levels in the spleen or lung at 24 hr after oral administration were higher than those of maximum plasma concentration($C_{max}$). The cumulative amounts of arsenic hexaoxide found in the urine by 48 hr after the administration of 50 mg/kg were 5-fold higher than those in the bile. However, the cumulative amounts in the feces were 10-fold higher compared with those of urine, suggesting that arsenic hexaoxide is mostly excreted in the feces. In conclusion, our observations indicated that arsenic hexaoxide was poorly absorbed from the gastro-intestinal tract to the blood circulation and transferred to tissues such as the spleen and lung at 24 hr after oral administration. Moreover, the majority of arsenic hexaoxide appears to be excreted in the feces by 48 hr after oral administration.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.88.1-88.1
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• 2003

CJ-11668 is a new potent and selective COX-2 inhibitor (IC$\sub$50/ COX-2 65nM; COX-l/COX-2 ratio 770). The pharmacokinetic profile of CJ-11668 (20 mg/kg, p.o.) in the rat was characterized by high bioavailability (90%) and long plasma half-life (11.7 hr) with low clearance (0.4 L/hr/kg). In the dog, the PK profiles (2 mg/kg, p.o.) also showed long plasma half-life (l7.9hr) with low clearance (0.5 L/hr/kg), and the bioavalability of 60%. The inhibition of CJ-11668 infive different cytochrome P450 isozymes (1A2, 2C9, 2C19, 2D6 and 3A4) was determined in vitro and had observed no significant effect. (omitted)

• Journal of fish pathology
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• v.35 no.1
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• pp.93-102
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• 2022

This study performed a trichlorfon (TCF) residue and pharmacokinetic analysis with Japanese eels, Anguilla japonica, to obtain baseline data to establish the maximum residue level (MRL) of TCF in A. japonica. After dipping A. japonica in 30 ppm and 150 ppm of TCF at 28℃ and 18℃, drug residue in the body was analyzed with LC-MS/MS, and these results were further analyzed with the PK solver program to obtain the pharmacokinetic parameters of TCF in the serum, muscles, and liver. The maximum concentrations (C_max) in the serum, muscles, and liver were 25.87-357.42, 129.91-1043.73, and 40.47-375.20, respectively, and the time to maximum concentration (T_max) was 0.13-1.32h, 1.17-3.34h, and 0.14-5.40h, respectively. The terminal elimination half-life (T_1/2) was 2.13-3.92h, 5.30-10.35h, and 0.65-13.81h, respectively. In the 30 mg/L concentration group, TCF was not detected in the serum of eels 96 hours after bathing, and was below the detection limit after 336 hours in muscle and liver. On the other hand, in the 150 mg/L concentration group, TCF was not detected in the serum of eels 336 hours after bathing, but was detected in muscle and liver at 336 hours. In conclusion, the results of this study would be useful in establishing the MRL of TCF in farmed A. japonica.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.105-114
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• 2020

Background: Exploring the pharmacokinetic (PK) changes of various active components of single herbs and their combinations is necessary to elucidate the compatibility mechanism. However, the lack of chemical standards and low concentrations of multiple active ingredients in the biological matrix restrict PK studies. Methods: A putative multiple reaction monitoring strategy based on liquid chromatography coupled with mass spectrometry (LC-MS) was developed to extend the PK scopes of quantification without resorting to the use of chemical standards. First, the compounds studied, including components with available reference standard (ARS) and components lacking reference standard (LRS), were preclassified to several groups according to their chemical structures. Herb decoctions were then subjected to ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry analysis with appropriate collision energy (CE) in MS² mode. Finally, multiple reaction monitoring transitions transformed from MS² of ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry were used for ultrahigh-performance liquid chromatography coupled with triple quadrupole mass spectrometry to obtain the mass responses of LRS components. LRS components quantification was further performed by developing an assistive group-dependent semiquantitative method. Results: The developed method was exemplified by the comparative PK process of single herbs Radix Ginseng (RG), Radix Polygala (RP), and their combinations (RG-RP). Significant changes in PK parameters were observed before and after combination. Conclusion: Results indicated that Traditional Chinese Medicine combinations can produce synergistic effects and diminish possible toxic effects, thereby reflecting the advantages of compatibility. The proposed strategy can solve the quantitative problem of LRS and extend the scopes of PK studies.

• Archives of Pharmacal Research
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• v.28 no.4
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• pp.476-482
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• 2005

We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats. To analyze ID-6105 levels in biological samples, we used an HPLC-based method which was validated in a pharmacokinetic study by suitable criteria. The concentrations of ID-6105 after the multiple administration for 5 days were not significantly different from the results after the single administration. The $t_{1/2\alpha}, t_{l/2\beta}, V_{dss}, and CL_{t}$ after the multiple administration were not significantly different from the values after the single administration. Moreover, the concentrations of ID-6105 1 min at day 1-5 after i.v. bolus multiple administration did not show the significant difference. Of the various tissues, ID-6105 mainly distributed to the kidney, lung, spleen, adrenal gland, and liver after i.v. bolus multiple administration. ID-6105 concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration decreased to low levels. ID-6105 was excreted largely in the bile after i.v. bolus multiple administration at the dose of 3 mg/kg. The amounts of ID-6105 found in the bile by 12 h or in the urine by 48 h after the administration were calculated to be $14.1\% or 4.55\%$ of the initial dose, respectively, indicating that ID-6105 is mostly excreted in the bile. In conclusion, ID-6105 was rapidly cleared from the blood and transferred to tissues, suggesting that ID-6105 might not be accumulated in the blood following i.v. bolus multiple dosages of 3 mg/kg every 24 h for 5 days. By 48 h after i.v. bolus administration, ID-6105 concentrations in various tissues had decreased to very low levels. The majority of ID-6105 appears to be excreted in the bile.

• The Journal of Korean Medicine
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• v.40 no.4
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• pp.1-15
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• 2019

Objectives: Here, we investigated the effects of concentrated and lyophilized powders Blue honeysuckle (BH) on the PK of tamoxifen, to establish the pharmacokinetics (PK) profiles as one of essential process in new drug development. Methods: After single oral treatment of 0.4 mg/ml of tamoxifen or tamoxifen 0.4 with BH 40, 20 and 10 mg/ml, the plasma were collected at 0.5 hr before administration, 0.5, 1, 2, 3, 4, 6, 8 and 24 hr after end of single or mixed formula treatment. Plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, t1/2 and MRTinf were analyzed using noncompartmental PK data analyzer programs. Results: Tamoxifen and BH 40 mg/ml did not induce any significant change on the plasma tamoxifen concentrations, while significant decreases were observed in tamoxifen and BH 10 mg/ml from 2 to 8 hr as compared with tamoxifen only, respectively. Furthermore, significant increases of Tmax in tamoxifen and BH 40 mg/ml, significant decreases of Cmax in tamoxifen and BH 20 mg/ml, significant decreases of AUC0-t, AUC0-inf and MRTinf in tamoxifen and BH 10 mg/ml were demonstrated as compared with tamoxifen only. Conclusion: Taken together, tamoxifen and BH 10 mg/ml induced significant decrease of the oral bioavailability of tamoxifen, while tamoxifen and BH 40 or 20 mg/ml did not critically influenced, suggesting formulated BH concentration-independencies. It, therefore, seems to be needed that pharmacokinetic study after repeated administration should be tested to conclude the effects of BH on the pharmacokinetics of tamoxifen.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.1
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• pp.107-115
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• 2017

Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the "fit for purpose" application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in $C_{max}$ of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.199-205
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• 2016

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration ($2-75{\mu}M$) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was $1.9{\mu}L/min$ while passive diffusion clearance was $0.31{\mu}L/min$. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as $C_{max}$ and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level.

• Journal of Pharmaceutical Investigation
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• v.38 no.4
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• pp.235-240
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• 2008

A sensitive and simple method of determining the plasma levofloxacin (LFX, CAS 100986-85-4) concentrations in human volunteers by liquid-liquid extraction were developed and validated by using a high-performance liquid chromatography/diode array detector. The method was also applied to pharmacokinetic study of LFX. LFX was orally administered to 8 healthy male Korean volunteers at single lowest dose of 200 mg, compared to the published reports in which more than 500 mg of LFX was orally administered. LFX in human plasma was determined. The detection limit of LFX was $0.05\;{\mu}g/mL$. $C_{max}$ value was $2.48{\pm}0.67\;{\mu}g/mL$. $AUC_{0{\to}24\;hr$} and $AUC_{0{\to}{\infty}}$ were $14.52{\pm}3.35\;{\mu}g/mL$ and $16.00{\pm}3.66\;{\mu}g{\cdot}hr/mL$, respectively. The terminal half-life was $6.87{\pm}0.46\;hr$. Our pharmacokinetic parameters were very consistent with that previously reported, showing good correlation between LFX doses and AUC ($r^2=0.995$). This method can be useful for the pharmacokinetics and bioequivalence study with relatively low dose for reducing the main side effects of LFX.