• Investigative Magnetic Resonance Imaging
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• v.17 no.4
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• pp.259-266
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• 2013

Purpose : To investigate the blood pharmacokinetics and bio-distribution of DTPA-bis-amide (L3) Gd(III) complexes. Materials and Methods: The pharmacokinetics and bio-distribution of Gd $(L3)(H_2O){\cdot}nH_2O$ were investigated in Sprague-Dawley rats after intravenous administration at a dose of 0.1 mmol Gd/kg. The Gd content in the blood, various tissues, and organs was determined by ICP-AES. Blood pharmacokinetic parameters were calculated using a two-compartment model. Results: The half-lives of ${\alpha}$ phase and ${\beta}$ phase Gd $(L3)(H_2O){\cdot}nH_2O$ were $2.286{\pm}0.11$ min and $146.1{\pm}7.5$ min, respectively. The bio-distribution properties reveal that the complex is mainly excreted by the renal pathway, and possibly excreted by the hepatobiliary route. The concentration ratio of Gd (III) was significantly higher in the liver and spleen than in other organs, and small amounts of Gd (III) ion were detected in the blood or other tissues of rats only after 7 days of intravenous administration. Conclusion: The MRI contrast agent Gd $(L3)(H_2O){\cdot}nH_2O$ provides prolonged blood pool retention in the circulation and then clears rapidly with minimal accumulation of Gd(III) ions. The synthesis of gadolinium complexes with well-balanced lipophilicity and hydrophilicity shows promise for their further development as blood pool MRI contrast agents.

• Journal of Soil and Groundwater Environment
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• v.9 no.1
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• pp.12-27
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• 2004

The contamination pattern of indoor air was simulated when groundwater dissolving benzene was used for household activities. Indoor exposure scenario consisted of inhalation, ingestion, and dermal absorption. Physiologically based pharmacokinetic (PBPK) model was used to analyze how benzene exposed to human body was distributed in internal organs. Main exposure pathways contributing total internal dose were inhalation and ingestion while the contribution of dermal absorption was very small. Man showed higher exposure rate than woman due to his higher breath rate. For a short-term exposure, benzene concentration in venous blood of SPT, RPT and liver changed rapidly while slowly did in venous blood of adipose tissue at a low concentration. For a long-term exposure, woman accumulated about 2.1 times higher than man. Most of benzene exposed to human body was removed by exhalation and metabolism at lung and liver, respectively. For inhalation and ingestion, the benzene removals by exhalation were 69.8 and 48.4%, respectively. Relative importance of removal mechanism was different according to the inflow displacement of benzene. The results obtained from this study would help understand exposure, distribution, and removal phenomena and make plans for the reduction of the health risk associated with the contaminated groundwater by various organic compounds.

• Journal of fish pathology
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• v.22 no.1
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• pp.91-95
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• 2009

The pharmacokinetic properties of oxytetracycline (OTC) were studied after intramuscular injection to cultured olive flounder, Paralichthys olivaceus. Plasma concentrations of OTC were determined after dosage of 12.5, 25 and 50 ㎎/㎏ body weight in olive flounder (average 600 g, $23{\pm}1{^{\circ}C}$). Plasma samples were taken at 3, 5, 10, 15, 24, 32, 48, 72, 120, 168, 240 and 360 h post-dose. With 25 and 50 ㎎/㎏, the peak plasma concentrations of OTC, which attained at 5 h post-dose, were 0.99 and 1.49 $\mu{g}/m\ell$, respectively. However, the peak plasma concentration of 12.5 ㎎/㎏ was 0.35 $\mu{g}/m\ell$ after 10 h post-dose. Plasma concentrations of OTC were not measurable at 360 h post-dose in all doses. The kinetic profile of absorption, distribution and elimination of OTC in plasma were analyzed fitting to a 1-compartment model by Win-Nonlin program. The following parameters were calculated for 12.5, 25 and 50 ㎎/㎏ body weight, respectively: AUC (the area under the concentration-time curve)?D���D24.98, 44.67 and 50.45 $\mu{g}$ $h/m\ell$ $T_{1/2}$ (half-life) ?D���D0.42, 0.59 and 0.41 h; $T_{max}$ (time for maximum concentration)?D���D8.46, 6.34 and 2.66 h; $C_{max}$ (maximum concentration)?D���D0.30, 0.63 and 1.13 $\mu{g}/m\ell$.

• Journal of fish pathology
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• v.23 no.2
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• pp.221-227
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• 2010

Effects of temperature ($13{\pm}1.5^{\circ}C$, $23{\pm}1.5^{\circ}C$) on the pharmacokinetic properties of oxolinic acid (OA) were studied after oral administration to cultured black rockfish, Sebastes schlegeli. Serum concentrations of OA were determined using HPLC-UV detector after a single dosage of 60 mg/kg body weight (average about 500 g). The peak serum concentrations of OA at $23{\pm}1.5^{\circ}C$ and $13{\pm}1.5^{\circ}C$ were $0.60{\mu}/ml$ at 30 h and $2.22{\mu}g/ml$ at 10 h post-dose, respectively. Better absorption of OA was noted at $13{\pm}1.5^{\circ}C$ compared to $23{\pm}1.5^{\circ}C$. The elimination of OA from serum was considerably faster at $23{\pm}1.5^{\circ}C$ than at $13{\pm}1.5^{\circ}C$. Both absorption and elimination of OA were affected significantly by temperature. The kinetic profile of absorption, distribution and elimination of OA in serum was analyzed by fitting to a two compartment model, with WinNonlin program. The AUC, Tmax and Cmax at $23{\pm}1.5^{\circ}C$ were $42.16{\mu}g{\cdot}h/m\ell$, 26.13 h and $0.43{\mu}g/ml$, respectively. The AUC, Tmax and Cmax at $13{\pm}1.5^{\circ}C$ were $131.98{\mu}g{\cdot}h/ml$, 8.81 h and $2.04{\mu}g/ml$, respectively.

• Journal of Pharmaceutical Investigation
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• v.25 no.3
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• pp.7-20
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• 1995

Taurine, a ${\beta}-amino$ acid, plays an important role as a neuromodulator and is necessary for the normal development of the brain. Since de novo synthesis of taurine in the brain is minimal and in vivo studies suggest that taurine dose not cross the blood-brain barrier, we examined whether the choroid plexus, the blood-cerebrospinal fluid (CSF) barrier, plays a role in taurine transport in the central nervous system. The uptake of $[^3H]-taurine$ into ATP depleted choroid plexus from rabbit was substantially greater in the presence of an inwardly directed $Na^+$ gradient taurine accumulation was negligible. A transient in side-negative potential gradient enhanced the $Na^+-driven$ uptake of taurine into the tissue slices, suggesting that the transport process is electrogenic, $Na^+-driven$ taurine uptake was saturable with an estimated $V_{max}$ of $111\;{\pm}\;20.2\;nmole/g/15\;min$ and a $K_M\;of\;99.8{\pm}29.9\;{\mu}M$. The estimated coupling ratio of $Na^+$ and taurine was $1.80\;{\pm}\;0.122.$ $Na^+-dependent$ taurine uptake was significantly inhibited by ${\beta}-amino$ acids, but not by ${\alpha}-amino$ acids, indicating that the transporter is selective for ${\beta}-amino$ acids. Since it is known that the physiological concentration of taurine in the CSF is lower than that in the plasma, the active transport system we characterized may face the brush border (i.e., CSF facing) side of the choroid plexus and actively transport taurine out of the CSF. Therefore, we examined in vivo elimination of taurine from the CSF in the rat to determine whether elimination kinetics of taurine from the CSF is consistent with the in vitro study. Using a stereotaxic device, cannulaes were placed into the lateral ventricle and the cisterna magna of the rat. Radio-labelled taurine and inulin (a marker of CSF flow) were injected into the lateral ventricle, and the concentrations of the labelled compounds in the CSF were monitored for upto 3 hrs in the cisterna magna. The apparent clearance of taurine from CSF was greater than the estimated CSF flow (p<0.005) indicating that there is a clearance process in addition to the CSF flow. Taurine distribution into the choroid plexus was at least 10 fold higher than that found in other brain areas (e. g., cerebellum, olfactory bulb and cortex). When unlabelled taurine was co-administered with radio-labelled taurine, the apparent clearance of taurine was reduced (p<0.0l), suggesting a saturable disposition of taurine from CSF. Distribution of taurine into the choroid plexus, cerebellum, olfactory bulb and cortex was similarly diminished, indicating that the saturable uptake of taurine into these tissues is responsible for the non-linear disposition. A pharmacokinetic model involving first order elimination and saturable distribution described these data adequately. The Michaelis-Menten rate constant estimated from in vivo elimination study is similar to that obtained in the in vitro uptake experiment. Collectively, our results demonstrate that taurine is transported in the choroid plexus via a $Na^+-dependent,saturable$ and apparently ${\beta}-amino$ acid selective mechanism. This process may be functionally relevant to taurine homeostasis in the brain.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9249-9258
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• 2014

Background: The encapsulation of curcumin (Cur) in polylactic-co-glycolic acid (PLGA) nanoparticles (Cur-NPs) was designed to improve its solubility and stability. Conjugation of the Cur-NPs with anti-P-glycoprotein (P-gp) antibody (Cur-NPs-APgp) may increase their targeting to P-gp, which is highly expressed in multidrugresistance (MDR) cancer cells. This study determined whether Cur-NPs-APgp could overcome MDR in a human cervical cancer model (KB-V1 cells) in vitro and in vivo. Materials and Methods: First, we determined the MDR-reversing property of Cur in P-gp-overexpressing KB-V1 cells in vitro and in vivo. Cur-NPs and Cur-NPs-APgp, in the range 150-180 nm, were constructed and subjected to an in vivo pharmacokinetic study compared with Cur. The in vitro and in vivo MDR-reversing properties of Cur-NPs and Cur-NPs-APgp were then investigated. Moreover, the stability of the NPs was determined in various solutions. Results: The combined treatment of paclitaxel (PTX) with Cur dramatically decreased cell viability and tumor growth compared to PTX treatment alone. After intravenous injection, Cur-NPs-APgp and Cur-NPs could be detected in the serum up to 60 and 120 min later, respectively, whereas Cur was not detected after 30 min. Pretreatment with Cur-NPs-APgp, but not with NPs or Cur-NPs, could enhance PTX sensitivity both in vitro and in vivo. The constructed NPs remained a consistent size, proving their stability in various solutions. Conclusions: Our functional Cur-NPs-APgp may be a suitable candidate for application in a drug delivery system for overcoming drug resistance. The further development of Cur-NPs-APgp may be beneficial to cancer patients by leading to its use as either as a MDR modulator or as an anticancer drug.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.70-81
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• 2000

DA-5018 is a synthetic capsaicin derivative under development as a non-narcotic a analgesic ag$\varepsilon$nt. DA-50 18 showed a potent analgesic activity against acute and chronic pain m model(Tablel, 2.), but it had a narrow margin of safety. DA-5018 did not bind to opioid(${\kappa}, {\delta}, {\mu}$), NKl, CGRP receptors in vitro and its analgesic effect was not antagonized by naloxone, a and it did not develop analgesic tolerance. In addition DA-5018 had no inhibitory effects against c cyclooxygenase and 5-lipooxygenase activities. DA-5018 significantly increased the relcase of substance P from the slices of the rat spinal cord. These results suggest that DA-50 18 is not a narcotic nor aspirin-like analgesic and the release of substance P is one of analgesic mechanism of action of DA-5018. We found that DA-5018 was almost ten times more potent and was at l least IOO-times less irritable compared to capsaicin. Accordingly development of topical formula was adopted. Topical formula was desiged and screened by flux test of DA-5018 using hairless mouse skin and several formulas were selected. With these topical formulas we a assessed the analgesic efficacy and carried out the toxicity, skin irritation and pharmacokinetic studies. In streptozotocin-induced hyperalgesic rat and 50 % galactose-fed hyperalgesic rat as diabetic pain models, DA-5018 cream increased the pain thresh이ds up to 77.0% and 24.4% respectively, while Zostrix-HP(capsaicin cream) incr$\varepsilon$as cd by 65.9% and 21.0%. DA-5018 c cream showed a good analgesic effect as welI in FCA-induced arthritic rat. DA-5018 cream did not show any toxicological signs in acute and chronic toxicity test and had little skin irritation in car swclIing and scratching t$\varepsilon$st. Pharmacokinetics of DA-50 18 were studied after topical application of ${14}^C$-Iabelled or unlabelIed DA-5018 cream. Plasma and skin concentrations c except applied skin wcre below the dctection limit and after 7-day cummulative application, plasma concentrations were also below detection limit DA-50 18 may have an advantag$\varepsilon$ ov$\varepsilon$r c capsaicin and is now being developed as a topical agent for the treatment of pains. DA-50 18 cream was approved for Korean IND and is now under a Phase II clinical study for arthritic pain a after finising Phase I study. DA-50 18 was also liscensed out to Stiefel Company in America in

• YAKHAK HOEJI
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• v.41 no.1
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• pp.60-73
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• 1997

In order to design a 24 hr sustained release preparation of sulindac for oral administration, fast release pellet (FR), slow release pellet (SR) and two combined formulation (1 : 1 and 1 : 2) were prepared. The pharmacokinetic effect of such preparations has been evaluated using rabbits as a suitable in vivo model, and tested in man. Dose determination was carried out using curve fitting according to RSTPJP II program. In bioavailability test using rabbit, AUCs of sulindac in a few designed formulations were similar to each other. $C_{max}$- of RF and SR were 1.8 times and 1.2 times higher, respectively, compared to that of combined formulation (FR:SR=1:1). While plasma concentration of FR and SR decreased rapidly, that of combined formulation (FR:SR 1:1) lasted at the level close to $C_{max}$ for 24 hrs. Plasma concentration of sulfide form from the combined pellet(FR:SR=1:1) lasted for 24 hrs, and its AUC value was 1.4-fold, 2.7-fold. and 1.2-fold greater than FR pellet, SR pellet and combined pellet (FR:SR 1 : 2). Thus, the combined pellet of 1:1 ratio was found to be the most effective for oral sustained release formulation. Bioavailability test in human showed that AUC of sulfide from TSRP (1 : 1) was approximately 1.5 times greater than total AUC of Immbaron$^{\circledR}$ administered twice in a day. While $T_{max}$ of sulfide from lmmbaron$^{\circledR}$ was 4.33 +/- 1.37 hr (lst administration) and 3.33 ${pm}$ 0.82 hr (2nd administration), respectively, that of sulfide from TSRP increased to 7.17 ${pm}$ 2.86 hr. Plasma concentration of sulfide from TSRP was sustained at more, than 1.0 ${\mu}g{\cdot}$hr/ml until 24 hrs after one dose administration. In addition, TSRP may decrease local adverse reaction in the stomach, since plasma concentration of sulfide from the combined pellet was low within 2hrs in the stomach. In conclusion, it is suggested that TSRP formulation may be effective for oral 24 hr sustained release formulation of sulindac dosing 300 ~ 350mg once a day.

• Journal of Ginseng Research
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• v.44 no.2
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• pp.247-257
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• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.160-165
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• 2018

Indobufen ($Ibustrin^{(R)}$), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using $NONMEM^{(R)}$ and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid $I_{max}$ model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.