• 제목/요약/키워드: Pharmacokinetic Model

검색결과 157건 처리시간 0.018초

Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo

  • Lee, Jongkook;Mandava, Suresh;Ahn, Sung-Hoon;Bae, Myung-Ae;So, Kyung Soo;Kwon, Ki Sun;Kim, Hyun Pyo
    • Biomolecules & Therapeutics
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    • 제28권4호
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    • pp.344-353
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    • 2020
  • This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPS-induced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders.

경구용 약물수송체로서의 팔미토일 치환 다당체로 코팅된 리포좀 (Palmitoylpolysaccharide-coated Liposomes As A Potential Oral Drug Carrier)

  • 한양희;이정우;최영욱
    • Journal of Pharmaceutical Investigation
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    • 제24권2호
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    • pp.73-83
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    • 1994
  • Applications of liposomes as a drug carrier for the oral delivery of poorly-absorbable macromolecular drugs have been limited, because of their instability in gastrointestinal environments including pH, bile salts, and digestive enzymes. Two polysaccharides, dextran(DX) and pullulan(PL), were introduced to the preformed liposomes in order to enhance the stability. Palmitoyl derivatives of polysaccharides, palmitoyldextran(PalDX) and palmitoylpullulan(PalPL), were synthesizd and introduced to the liposomes during preparation for the same purpose of stability. The effects of these polysaccharides coating were evaluated basically by physical properties of particle size distribution and optical microscopy, then compared with uncoated liposomes by the observations of both in vitro stability and in vovo absorption characteristics. The geometric mean diameters of polysaccharide-coated liposomes were greater than that of uncoated liposome, showing the outermost polysaccharide-coated layer under the optical microscopy. In vitro stabilities of uncoated or polysaccharides-coated liposomes were measured by turbidity changes in various pH buffer solutions containing sodium choleate as bile salts. While uncoated liposome was very sensitive to bile salts, polysaccharides-coated liposomes were stable in relatively higher concentrations of sodium choleate, giving the results of better stability of PalDX- and PalPL-coated liposomes than that of DX- and PL-coated liposomes. After liposomal encapsulation of acyclovir(ACV), an antiviral agent as a model drug, it has been administered orally to rats as dose of ACV 40 mg/kg. Plasma concentrations of ACV were assayed by HPLC and analyzed by model-independent pharmacokinetics. Pharmacokinetic parameters of Cmax, tmax, and [AUC] have been compared.

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Soybean Trypsin Inhibitor와 황산 콘드로이친 포합체의 약리 효과 평가 (Evaluation of Pharmacological Effect of Soybean Trypsin Inhibitor-Chondroitin Sulfate Conjugates)

  • 최윤림;남현규;신영희
    • Journal of Pharmaceutical Investigation
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    • 제30권3호
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    • pp.159-166
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    • 2000
  • Kunitz-type soybean trypsin inhibitor (SBTI) and chondroitin sulfate (A, and C type) were conjugated using sodium periodate method. And the physicochemical, pharmacokinetic properties and immunogenecity of the conjugates (Chon-A-SBTI or Chon-C-SBTI) were characterized. We expected the conjugation using chondroitin sulfate to reduce the immunogenecity and to improve the pharmacological effect. As the results, the mean molecular weight of the conjugate highly increased. After I.V. injection of the radiolabeled conjugates or native SBTI into mice, it was found that native SBTI showed rapid elimination from plasma, whereas Chon-A-SBTI and Chon-C-SBTI were slowly eliminated. Organ distribution of the two agents at 30 min after I.V. injection was different : Chon-A-SBTI or Chon-C-SBTI accumulated to a large extent in the liver (13% in Chon-A-SBTI and 16% in Chon-C-SBTI), whereas native SBTI was taken up more rapidly by the kidney (107% dose/g of tissue) and excreated into the urine (26%). In addition we evaluated the therapeutic value of the conjugates by using the sublethal septic shock model caused by pseudomonal elastase and tested the immunogenecity by passive cutaneous anaphylaxis shock (PCA). The conjugates were more effective than native SBTI against pseudomonal elastase induced septic shock in guinea pig. In case of the conjugates, the pharmacological and therapeutic effect lasted over 3 hours long. In immunogenecity test, both of the conjugates showed the reduction of their immunogenecity, especially Chon-A-SBTI looked most effective.

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EC50 of Remifentanil to Prevent Propofol Injection Pain

  • Hong, Hun Pyo;Ko, Hyun Min;Yoon, Ji Young;Yoon, Ji Uk;Park, Kun Hyo;Roh, Young Chea
    • 대한치과마취과학회지
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    • 제13권3호
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    • pp.89-94
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    • 2013
  • Background: Various strategies have been studied to reduce the propofol injection pain. This study was designed to find out effect-site target concentration (Ce) of remifentanil at which there was a 50% probability of preventing the propofol injection pain (EC50). Methods: Anesthesia was induced with a remifentanil TCI (Minto model). The Ce of remifentanil for the first patient started from 2.0 ng/ml. The Ce of remifentanil for each subsequent patient was determined by the response of the previous patient by Dixon up-and-down method with the interval of 0.5 ng/ml. After the remifentanil reached target concentrations, propofol was administered via a target-controlled infusion system based on a Marsh pharmacokinetic model using a TCI device (Orchestra$^{(R)}$; Fresenius-Vial, Brezins, France). The dose of propofol was effect site target-controlled infusion (TCI) of $3{\mu}g/ml$. Results: The EC50 of remifentanil to prevent the propofol injection pain was $1.80{\pm}0.35ng/ml$ by Dixon's up and down method. Conclusions: The EC50 of remifentanil to blunt the pain responses to propofol injection was $1.80{\pm}0.35ng/ml$ for propofol TCI anesthesia.

雙和湯이 四鹽化炭素에 의한 肝障害 Rat에서 Sulfobromophthalein의 體內動態에 미치는 영향 (Effects of a Chinese Traditional Medicine, Ssang Wha Tang, on the Pharmacokinetics of Sulfobromophthalein in the Rats of Hepatic Failure Induced by Carbon Tetrachloride)

  • 안병락;김신근;심창구;정연복
    • 약학회지
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    • 제28권4호
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    • pp.207-215
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    • 1984
  • Effects of Ssang Wha Tang (SWT), a blended Chinease traditional medicine, on the pharmacokinetics of sulfobromophthalein (BSP) in the rats of hepatic failure induced by carbon tetrachloride were examined. The disposition of plasma BSP in carbon tetrachloride-treated rats (Group I) and in carbon tetrachloride+SWT-treated rats (Group II) followed a three-compartment model, while those in control group followed two-compartment model. GOT, GPT level and some pharmacokinetic paramiters like plasma clearance but except distribution volume (Vdss) recovered in Group II compared to Group I. Therefore, SWT seemed to have an apparent restoring effect of hepatic function damaged by carbon tetrachloride treatment. From the fact that Vdss of BSP in Group II was considered as an one of the probable mechanisms. More intensive increase in BSP-free fraction ($f_p$) in Group II than that in Group I might also explain the increases of BSP clearance and Vdss in Group II compared to Group I. Assuming no changes in hepatic plasma flow(Q) in each group, hepatic intrinsic clearance($CL^h_{int}$) decreased in Group I did not recovered not at all in Group II. Therefore SWT seemed not to have any restoring effect of true hepaticfunction to biotransform and excrete BSP, and the apparent restoring effect of SWT might be due only to the replacement of BSP-plasma protein binding. Whether $f_p$ is actually higer in Group II than in Group I, and Q is constant in each group are being examined in our laboratory. The changes of Q, which might lead to another conculusions, also should be taken into consideration to clarify the apparent hepatorestoring effect of SWT.

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닭에서 ciprofloxacin의 체내 동태에 관한 연구 (Pharmacokinetics of ciprofloxacin in chickens)

  • 강환구;조명행;이항;한명국;손성완;김재학;이재진
    • 대한수의학회지
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    • 제35권3호
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    • pp.471-480
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    • 1995
  • The purpose of this experiment was to develop a simple and reliable HPLC method for the detection of ciprofloxacin in chicken serum and to provide a basic data on pharmacokinetic parameters after oral and intramuscular administration. The results obtained were as follows: 1. 0.2% meta-phosphoric acid: acetonitrile(7:3, v/v) solution had a high and regular recovery rates and was selected as an extraction solution. 2. The recovery rates of ciprofloxacin were 83-97% with the selected solution in chicken serum and the detection limit was 50ng/ml in serum. 3. Ka(abosorption rate constant) were 3.652 1/h in fasted group and 0.880 1/h in non-fasted group, and Ke (elimination rate constant) were 0.061 1/h and 0.133 1/h, respectively. 4. The highest concentration in serum after intramuscular injection was 840ng/ml within 15-30min and 160-324ng/ml in 1.1-3.2 hours after oral administration. 5. The time course of blood concentration fits well into a 2 compartment model. 6. On oral administration of ciprofloxacin with feed, ciprofloxacin was absorbed more slowly and the amount of absorbed was smaller than that of in fasted chickens. 7. Blood concentration of ciprofloxacin increased in a dose-dependent manner after intramusclular and oral administraiton.

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토끼의 성차가 sulfamethazine의 약동학 및 대사산물 생성에 미치는 영향 (Effect of gender on the pharmacokinetics and metabolite formation of sulfamethazine in the rabbit)

  • 윤효인;박일현
    • 대한수의학회지
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    • 제32권1호
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    • pp.35-39
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    • 1992
  • Sulfamethazine(SMZ)은 수의임상에서 감염증 치료 및 예방목적으로 많이 사용되고 있을 뿐 아니라 가축의 생산성 향상을 위해 남용되고 있는 주요한 항균제의 하나이다. SMZ의 생체내 대사 및 약물동태학적 특성은 동물의 종차에 따라 상이함이 잘 알려져 있으나 주요 실험동물 및 경제동물인 토끼에서 조사된 바는 매우 드물다. 한편 성차에 따른 약물대사의 차이는 rat를 비롯한 여러 동물에서 인정되고 있는데 대체로 숫컷이 암컷에 비해 대사능이 활발한 것으로 알려져 있다. 그러나 산양에서의 SMZ의 대사는 오히려 암컷이 더 활발하다는 보고도 있어, 여러 동물종에서 일률적으로 성차에 따른 약물대사를 설명할 수가 없다. 초식성의 습성을 가지고 있는 토끼에 있어 성차에 따른 SMZ의 대사 및 약물동태학적 특성이 다른 초식성 동물인 산양의 경우와 동일한 경향을 보이는지는 매우 흥미 있다할 것이다. New Zealand White 토끼에 SMZ을 이정맥에 35mg/kg를 주사한 후 미리 정해진 시간에 수거된 혈장 및 뇨(24시간)를 HPLC를 이용하여 분석하여 아래와 같은 약물동태학 및 대사적 특성을 얻었다. 1. 토끼에서의 SMZ의 주요 대사경로는 아세틸화$(N_4AcSMZ)$이었다. 두개의 수산화 대사산물(50HSMZ, $6CH_2OHSMZ$)도 생성되어 수산화 경로가 있음을 확인하였으나 양적인 관심에서 주요하지 않았다. 2. 토끼에서의 SMZ의 각 대사산물의 생성은 암수간의 성차에 따른 차이가 인정되지 않았다. 3. SMZ을 토끼의 이정맥에 투여(35mg/kg)하였을 때의 약물동태학적 특성은 1구1차 지수형 배설형태로 설명이 가능하였으며 암수에 따른 성차가 인정되지 않았다. 4. SMZ는 신속하게 $N_4AcSMZ$로 대사되었으며, $N_4AcSMZ$의 체외배설은 SMZ에 비해 매우 느렸으며 성차에 따른 배설속도의 차이를 인정할 수 없었다.

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Inhalation of panaxadiol alleviates lung inflammation via inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells

  • Yifan Wang;Hao Wei;Zhen Song;Liqun Jiang;Mi Zhang;Xiao Lu;Wei Li;Yuqing Zhao;Lei Wu;Shuxian Li;Huijuan Shen;Qiang Shu;Yicheng Xie
    • Journal of Ginseng Research
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    • 제48권1호
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    • pp.77-88
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    • 2024
  • Background: Lung inflammation occurs in many lung diseases, but has limited effective therapeutics. Ginseng and its derivatives have anti-inflammatory effects, but their unstable physicochemical and metabolic properties hinder their application in the treatment. Panaxadiol (PD) is a stable saponin among ginsenosides. Inhalation administration may solve these issues, and the specific mechanism of action needs to be studied. Methods: A mouse model of lung inflammation induced by lipopolysaccharide (LPS), an in vitro macrophage inflammation model, and a coculture model of epithelial cells and macrophages were used to study the effects and mechanisms of inhalation delivery of PD. Pathology and molecular assessments were used to evaluate efficacy. Transcriptome sequencing was used to screen the mechanism and target. Finally, the efficacy and mechanism were verified in a human BALF cell model. Results: Inhaled PD reduced LPS-induced lung inflammation in mice in a dose-dependent manner, including inflammatory cell infiltration, lung tissue pathology, and inflammatory factor expression. Meanwhile, the dose of inhalation was much lower than that of intragastric administration under the same therapeutic effect, which may be related to its higher bioavailability and superior pharmacokinetic parameters. Using transcriptome analysis and verification by a coculture model of macrophage and epithelial cells, we found that PD may act by inhibiting TNFA/TNFAR and IL7/IL7R signaling to reduce macrophage inflammatory factor-induced epithelial apoptosis and promote proliferation. Conclusion: PD inhalation alleviates lung inflammation and pathology by inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells. PD may be a novel drug for the clinical treatment of lung inflammation.

Pharmacokinetics of Uridine Following Ocular, Oral and Intravenous Administration in Rabbits

  • Kim, Eunyoung;Kang, Wonku
    • Biomolecules & Therapeutics
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    • 제21권2호
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    • pp.170-172
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    • 2013
  • The pyrimidine nucleoside uridine has recently been reported to have a protective effect on cultured human corneal epithelial cells, in an animal model of dry eye and in patients. In this study, we investigate the pharmacokinetic profile of uridine in rabbits, following topical ocular (8 mg/eye), oral (450 mg/kg) and intravenous (100 mg/kg) administration. Blood and urine samples were serially taken, and uridine was measured by high-performance liquid chromatography-tandem mass spectrometry. No symptoms were noted in the animals after uridine treatment. Uridine was not detected in either plasma or urine after topical ocular administration, indicating no systemic exposure to uridine with this treatment route. Following a single intravenous dose, the plasma concentration of uridine showed a bi-exponential decay, with a rapid decline over 10 min, followed by a slow decay with a terminal half-life of $0.36{\pm}0.05$ h. Clearance and volume of distribution were $1.8{\pm}0.6$ L/h/kg and $0.58{\pm}0.32$ L/kg, respectively. The area under the plasma concentration-time curves (AUC) was $59.7{\pm}18.2{\mu}g{\cdot}hr/ml$, and urinary excretion up to 12 hr was ~7.7% of the dose. Plasma uridine reached a peak of $25.8{\pm}4.1{\mu}g/ml$ at $2.3{\pm}0.8$ hr after oral administration. The AUC was $79.0{\pm}13.9{\mu}g{\cdot}hr/ml$, representing ~29.4% of absolute bioavailability. About 1% of the oral dose was excreted in the urine. These results should prove useful in the design of future clinical and nonclinical studies conducted with uridine.

Nano-sized Drug Carriers and Key Factors for Lymphatic Delivery

  • Choi, Ji-Hoon;Lee, Yong-Bok
    • Journal of Pharmaceutical Investigation
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    • 제40권spc호
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    • pp.75-82
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    • 2010
  • Specific diseases like cancer and acquired immune deficiency syndrome (AIDS) occur at various organs including lymphatics and spread through lymphatic system. Thus, if therapeutic agents for such diseases are more distributed or targeted to lymphatic system, we can obtain several advantages like reduction of systemic side effect and increase of efficacy. For these reasons, much interest has been focused on the nature of lymphatics and a lot of studies for lymphatic delivery of drugs have been carried out. Because lymphatics consist of single layer endothelium and have high permeability compared with blood capillaries, especially, the studies using nano-sized carriers have been performed. Polymeric nano-particle, liposome, and lipid-based vehicle have been adopted for lymphatic delivery as carriers. According to the administration route and the kind of carrier, the extent of lymphatic delivery efficiency of nano-sized carriers has been changed and influenced by several factors such as size, charge, hydrophobicity and surface feature of carrier. In this review, we summarized the key factors which affect lymphatic uptake and the major features of carriers for achieving the lymphatic delivery. Lymphatic delivery of drug using nano-sized carriers has many fold improved ability of lymphatic delivery compared with that of conventional dosage forms, but it has not shown whole lymph selectivity yet. Even though nano-sized carriers still have the potential and worth to study as lymphatic drug delivery technology as before, full understanding of delivery mechanism and influencing factors, and setting of pharmacokinetic model are required for more ideal lymphatic delivery of drug.