• Title/Summary/Keyword: Drug Distribution

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Pharmacokinetics of Astromicin Following a Single Intravenous Infusion in Healthy Korean Subjects (정상성인 한국인에서 아스트로마이신 1회 점적 주사후 약물동태학적 평가)

  • Bok, Hae Sook;Choi, Kyung Eob;Kim, Yeon Hwa;Peck, Kyong Ran;Song, Jae Hoon
    • Korean Journal of Clinical Pharmacy
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    • v.13 no.2
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    • pp.55-58
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    • 2003
  • Astromicin is an aminoglycoside antiviotic that is structually different from conventional aminoglycosides. Astromicin has been shown to be active against aerobic Gram-negative bacilli. The pharmacokinetics of astromicin were determined in 12 healthy volunteers ($65.5\pm5.23\;kg$ of body weight) following a 30-min continuous intravenous infusion at a dose of 200 mg. The plasma and urine samples were collected up to 24 h and drug concentrations were measured by a bioassay using Bacillus subtilis. Pharmacokinetic parameters were calculated by fitting individual concentration-time curve to a one-exponential decay model. The plasma levels were $16.9\pm1.68\;and\;1.05\pm0.346\l{\mu}g/ml$ at 0 h and 8 h after the infusion, respectively. The elimination half-life of astromicin was $1.86\pm0.360\;h$ The volume of distribution was $0.182\pm0.0164\;L/kg$, and the total body clearance was $5.25\pm1.74\;L/h$. These pharmacokinetic parameters were similar to these of gentamicin, tobramycin, and amikacin. Therefore, it is recommended that therapeutic drug monitoring of astromicin could be conducted in a similar fashion as the other aminoglycosides.

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Effect of Cimetidine on Theophylline Disposition and Metabolic Pathways (Cimetidine의 Theophylline 약동학 및 대사과정에 미치는 효과에 관한 연구)

  • Jang, In-Jin;Lee, Sun-Hee;Shin, Jae-Gook;Shin, Sang-Goo;Park, Chan-Woong
    • The Korean Journal of Pharmacology
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    • v.26 no.1
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    • pp.83-90
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    • 1990
  • The effect of cimetidine on theophylline metabolism was examined in dogs. Single dose intravenous theophylline kinetic studies were performed in cross-over manner before and after one week intravenous cimetidine (30 mg/kg/day) treatment. Cimetidine decreased theophylline clearance by an average of 31% (p<0.05) and prolonged theophylline half-li fe by an average of 29% (p<0.01) compared to those in control peirods. However, steady-state volume of distribution and protein binding of theophylline were not changed significantly. Twenty-four hours urinary excretion of 3-methylxanthine, 1-methyluric acid and 1,3-dimethyluric acid, which are the major metabolites of theophylline, were all decreased after cimetidine treatment, whereas the excreted fractions of individual metabolites were unchanged by cimetidine. From the above data, it could be susggested that cimetidine decreases theophylline clearance and prolongs the half-life by non-specific inhibition of the demethylations and 8-hydroxylation pathways.

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Sustained Release of Water-Soluble Blue Dextran from PLGA Nanoparticles (PLGA 나노파티클로부터 수용성 블루 덱스트란의 서방성 방출)

  • Ryu, Sang-Hwa;Hwang, Sung-Joo;Park, Jeong-Sook
    • Journal of Pharmaceutical Investigation
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    • v.36 no.2
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    • pp.109-114
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    • 2006
  • Biodegradable poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles were developed for sustained delivery of water-soluble macromolecules. PLGA nanoparticles were fabricated by spontaneous emulsification solvent diffusion method generating negatively charged particles and heterogeneous size distribution. As a model drug, blue dextran was encapsulated in PLGA nanoparticles. In addition, nanoparticles were also prepared with varying ratio of poloxamer 188 (P188) and poloxamer 407 (P407), and coating with poly(vinyl alcohol) (PVA). Then, the particle size, zeta potential and encapsulation efficiency of nanoparticles containing blue dextran were studied. In vitro release of blue dextran from nanoparticles was also investigated. The surface and morphology of nanoparticles were characterized by scanning electron microscopy (SEM). In case of nanoparticles prepared with PLGA, P407, and different organic solvents, particle size was in the range of $230{\sim}320\;nm$ and zeta potentials of nanoparticles were negative. The SEM images showed that ethyl acetate is suitable for the formulation of PLGA nanoparticles with good appearance. Moreover, ethyl acetate showed higher encapsulation efficiency than other solvents. The addition of P188 to formulation did not affect the particle size of PLGA nanoparticles but altered the release patterns of blue dextran from nanoparticles. However, PVA, as a coating material, altered the particle size with increasing the PVA concentration. The nanoparticles were physically stable in the change of particle size during long-term storage. From the results, the PLGA nanoparticles prepared with various contents of poloxamers and PVA, could modulate the particles size of nanoparticles, in vitro release pattern, and encapsulation of water-soluble macromolecules.

Study on production process of graphite for biological applications of 14C-accelerator mass spectrometry

  • Ha, Yeong Su;Kim, Kye-Ryung;Cho, Yong-Sub;Choe, Kyumin;Kang, Chaewon
    • Journal of Radiopharmaceuticals and Molecular Probes
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    • v.6 no.1
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    • pp.20-26
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    • 2020
  • Accelerator mass spectrometry (AMS) is a powerful detection technique with the exquisite sensitivity and high precision compared with other traditional analytical techniques. Accelerator mass spectrometry can be widely applied in the technique of radiocarbon dating in the fields of archeology, geology and oceanography. The ability of accelerator mass spectrometry to measure rare 14C concentrations in microgram and even sub-microgram amounts suggests that extension of 14C-accelerator mass spectrometry to biomedical field is a natural and attractive application of the technology. Drug development processes are costly, risky, and time consuming. However, the use of 14C-accelerator mass spectrometry allows absorption, distribution, metabolism and excretion (ADME) studies easier to understand pharmacokinetics of drug candidates. Over the last few decades, accelerator mass spectrometry and its applications to preclinical/clinical trials have significantly increased. For accelerator mass spectrometry analysis of biological samples, graphitization processes of samples are important. In this paper, we present a detailed sample preparation procedure to apply to graphitization of biological samples for accelerator mass spectrometry.

Imperatorin is Transported through Blood-Brain Barrier by Carrier-Mediated Transporters

  • Tun, Temdara;Kang, Young-Sook
    • Biomolecules & Therapeutics
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    • v.25 no.4
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    • pp.441-451
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    • 2017
  • Imperatorin, a major bioactive furanocoumarin with multifunctions, can be used for treating neurodegenerative diseases. In this study, we investigated the characteristics of imperatorin transport in the brain. Experiments of the present study were designed to study imperatorin transport across the blood-brain barrier both in vivo and in vitro. In vivo study was performed in rats using single intravenous injection and in situ carotid artery perfusion technique. Conditionally immortalized rat brain capillary endothelial cells were as an in vitro model of blood-brain barrier to examine the transport mechanism of imperatorin. Brain distribution volume of imperatorin was about 6 fold greater than that of sucrose, suggesting that the transport of imperatorin was through the blood-brain barrier in physiological state. Both in vivo and in vitro imperatorin transport studies demonstrated that imperatorin could be transported in a concentration-dependent manner with high affinity. Imperatorin uptake was dependent on proton gradient in an opposite direction. It was significantly reduced by pretreatment with sodium azide. However, its uptake was not inhibited by replacing extracellular sodium with potassium or N-methylglucamine. The uptake of imperatorin was inhibited by various cationic compounds, but not inhibited by TEA, choline and organic anion substances. Transfection of plasma membrane monoamine transporter, organic cation transporter 2 and organic cation/carnitine transporter 2/1 siRNA failed to alter imperatorin transport in brain capillary endothelial cells. Especially, tramadol, clonidine and pyrilamine inhibited the uptake of [$^3H$]imperatorin competitively. Therefore, imperatorin is actively transported from blood to brain across the blood-brain barrier by passive and carrier-mediated transporter.

Free-standing Three Dimensional Graphene Incorporated with Gold Nanoparticles as Novel Binder-free Electrochemical Sensor for Enhanced Glucose Detection

  • Bui, Quoc Bao;Nguyen, Dang Mao;Nguyen, Thi Mai Loan;Lee, Ku Kwac;Kim, Hong Gun;Ko, Sang Cheol;Jeong, Hun
    • Journal of Electrochemical Science and Technology
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    • v.9 no.3
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    • pp.229-237
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    • 2018
  • The electrochemical sensing performance of metal-graphene hybrid based sensor may be significantly decreased due to the dissolution and aggregation of metal catalyst during operation. For the first time, we developed a novel large-area high quality three dimensional graphene foam-incorporated gold nanoparticles (3D-GF@Au) via chemical vapor deposition method and employed as free-standing electrocatalysis for non-enzymatic electrochemical glucose detection. 3D-GF@Au based sensor is capable to detect glucose with a wide linear detection range of $2.5{\mu}M$ to 11.6 mM, remarkable low detection limit of $1{\mu}M$, high selectivity, and good stability. This was resulted from enhanced electrochemical active sites and charge transfer possibility due to the stable and uniform distribution of Au NPs along with the enhanced interactions between Au and GF. The obtained results indicated that 3D-GF@Au hybrid can be expected as a high quality candidate for non-enzymatic glucose sensor application.

Simultaneous Determination of Asperosaponins and Iridoid Glycosides from Dipsaci Radix by Using LC-ESI-MS Spectrometry (속단(Dipsaci Radix) 중 Asperosaponins 및 Iridoid glycosides의 LC-ESI-MS에 의한 동시분석)

  • Cho, Hwang-Eui;Son, In-Seop;Kim, Sun-Cheun;Son, Kun-Ho;Woo, Mi-Hee;Moon, Dong-Cheul
    • Korean Journal of Pharmacognosy
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    • v.43 no.2
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    • pp.137-146
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    • 2012
  • Dipsaci Radix (Dipsacaceae) has been used as a tonic, an analgesic, anti-inflammatory and anti-complement agents in traditional herbal medicine for the therapy of low back pain, knee pain, rheumatic arthritis, traumatic hematoma, and bone fractures. A high-performance liquid chromatography-electrospray ionization-mass spectrometric method (HPLC-ESI-MS) was developed for the simultaneous quantitation method of the five compounds from the herbal drug: asperosaponin VI and asperosaponin XII (terpene glycosides), sweroside, loganin and dipsacus A(iridoid glycosides). HPLC separation of the analytes was achieved on a C18 column ($150{\times}2.0$ mm i.d., 5 ${\mu}m$) using the aqueous methanol containing 5 mM ammonium acetate with gradient flow of the mobile phase. Detection of the analytes was performed by positive ion electrospray ionization, and selected ion monitoring was used for data acquisition using m/z corresponding molecular adduct ion, $[M+NH_4]^+$ and $[M+H]^+$. Calibration graphs showed good linearity ($r^2$=0.9997) over the wide range of the analytes; intra- and inter-day precisions (RSD, %) were within 9.1% and the accuracy between 94.0-111.0%. Recoveries of the analytes through the assay procedure were in the range of 93.7-110.8%. Analytical results of the herbal drugs of Dipsaci Radix (17 samples) show wide distribution of the five marker compounds and clear difference of the species from Phlomidis Radix (4 samples). The developed method would provide a practical guide for the quality control of the herbal drug.

Cytotoxicity, Stability and Antitumor Activity of 5-Fluorouracil Prodrugs Entrapped in Liposomes (리포좀에 봉입한 5-플루오로우라실 프로드럭의 세포독성, 안정성 및 항암효과)

  • Lee, Gye-Won;Ji, Ung-Gil
    • YAKHAK HOEJI
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    • v.40 no.5
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    • pp.522-531
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    • 1996
  • 5-fluorouracil(5-FU) derivatives synthesized with four N-acyloxycarbonyl group such as 1-(N-t-butyloxycarbonyl)glycyloxymethyl-5-FU(BGFU), 1-(N-t-butyloxycarbonyl)leucyloxymethy l-5-FU(BLFU), 1-(N-t-carbobenzyloxymethyl)glycyoxymethyl-5-FU(CGFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU) were entrapped into liposomes with different lipid compositions. The entrapment efficiency and release rate of drugs from each liposomes were evaluated. The particle size of liposomes, cytotoxicity and stability of drug-entrapped in liposomes were evaluated. The entrapment efficiency in 5-FU derivatives liposomes was dependent on the lipophilicity of N-acyloxymethyl derivatives. The drug entrapment efficiency also increased on the content of lipid increased up to 200mcmol of lipid per milliliter of liposomal solution. However, inclusion of additives such as cholesterol, dicetylphosphate and stearylamine decreased the entrapment efficiency. The mean particle size and size distribution were varied with lipid compositions and lipophilicity of prodrugs. The release rates of drugs from liposomes were not affected by additives, but those of BGFU and CGFU entrapped in liposomes with cholesterol decreased. Cytotoxicity of BLFU and CLFU entrapped in liposomes decreased by 3~5 fold compared with those of free two prodrugs. Liposome-entrapped 5-FU prodrugs were more stable either at pH 7.4 or in human plasma. Especially, 5-FU prodrugs entrapped in liposome with dipalmitoylphosphatidylcholine(DMPC) was the most stable in human plasma. Compared with free BLFU, BLFU entrapped in DMPC liposome showed a superior antitumor activity at all doses used. In contrast, CLFU entapped in liposomes were more toxic than free prodrug.

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Permeability of a Capsaicin Derivative $[{14}^C]DA-5018$ to Blood-Brain Barrier Corrected with HPLC Method

  • Kang, Young-Sook;Kim, Jong-Mi
    • Archives of Pharmacal Research
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    • v.22 no.2
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    • pp.165-172
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    • 1999
  • In the present work , the transport mechanism of a capsaicin derivative, DA-5018, through blood-brain barrier (BBB) has been investigated to evaluate the feasibility of potential drug development. The result of pharmacokinetic parameters obtained from the intravenous injection of plasma volume marker,$[3^H]RSA$ and $[{14}^C]DA-5018$, indicated that both AUC, area under the plasma concentration curve and VD, volume of distribution in brain of $[3^H]RSA$ agreed with those reported ($1620{\pm}10 $percentage injected dose minute per milliliter (%IDmin/ml) and $12.0{\pm}0.1{\mu}l/g$, respectively). Elimination half-life and AUC of $[{14}^C]DA-5018$is corrected by the PHLC analysis, 19.6$\pm$1.2 min and 7.69$\pm$0.85% IDmin/ml, respectively. The metabolic rate of $[{14}^C]DA-5018$was very rapid. The blood-brain barrier permeability surface area (PS) product of $[{14}^C]DA-5018$ was calculated to be 0.24$\pm$0.05 $\mu$l/min/g. The result of internal carotid artery perfusion and capillary depletion suggested that [14C]DA-5018 pass through BBB with the time increasingly. Investigation of transport mechanism of $[{14}^C]DA-5018$ using agonist and antagonist suggested that vanilloid (capsaicin) receptor did not exist in the BBB, and nutrient carrier system in the BBB has no effect on the transport of DA-5018. In conclusion, despite the fact that penetration of DA-5018 through BBB is significant, the intact drug found in the brain tissue is small because of a rapid metabolism. Therefore, for the central analgesic effect of DA-5018, the method to increase the metabolic stability in plasma and the brain permeability should be considered.

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Pharmacokinetic-Pharmacodynamic Modeling for the Relationship between Glucose-Lowering Effect and Plasma Concentration of Metformin in Volunteers

  • Lee, Shin-Hwa;Kwon, Kwang-il
    • Archives of Pharmacal Research
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    • v.27 no.7
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    • pp.806-810
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    • 2004
  • Metformin is a biguanide antihyperglycemic agent often used for the treatment of non-insulin dependent diabetics (NIDDM). In this study, the pharmacokinetics and pharmacodynamics of metformin were investigated in Korean healthy volunteers during a fasting state for over 10 h. In order to evaluate the amount of glucose-lowering effect of metformin, the plasma concentrations of glucose were measured for a period of 10 h followed by the administration of metformin (oral 500 mg) or placebo. In addition, the concentration of metformin in blood samples was determined by HPLC assay for the drug. All volunteers were consumed with 12 g of white sugar 10 minutes after drug intake to maintain initial plasma glucose concentration. The time courses of the plasma concentration of metformin and the glucose-lowering effect were analyzed by nonlinear regression analysis. The estimated $C_{max}$, $T_{max}$, $CL_{t}$/F (apparent clearance), V/F(apparent volume of distribution), and half-life of metformin were 1.42$\{pm}$0.07 $\mu\textrm{g}$/mL, 2.59$\{pm}$0.18h, 66.12$\{pm}$4.6 L/h, 26.63 L, and 1.54 h respectively. Since a significant counterclock-wise hysteresis was found for the metformin concentration in the plasma-effect relationship, indirect response model was used to evaluate pharmacodynamic parameters for metformin. The mean concentration at half-maximum inhibition $IC_{50}$, $k_{in}$, $k_{out}$ were 2.26 $\mu\textrm{g}$/mL, 83.26 $H^{-1}$, and 0.68 $H^{-1}$, respectively. Therefore, the pharmacokinetic-pharmacodynamic model may be useful in the description for the relationship between plasma concentration of metformin and its glucose-lowering effect.