• 약학회지
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• 제42권4호
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• pp.437-446
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• 1998

The distribution, metabolism and excretion of CKD-602{20(S)-7-[2-(N-Isopropylamino)ethyl]camptothecin HCI), a new camptothecin derivative, were investigated in rats after a sing le administration of CKD-602. 1. The tissue levels of CKD-602 given to mice by the intravenous route at a dose of 20mg/kg were the highest in intestine, followed in descending order by kidney, liver, stomach,lung, heart, spleen and plasma. The concentrations of CKD-602 after 24hrs decreased to less than 2% of the peak level in most tissues except the skin. The urinary and fecal excretion of CKD-602 were 47.6% and 44.4% of the administered dose, respectively, with 0.7% remaining in the rinse. 2. After administration of CKD-602 at 10mg/kg in rats, metabolism of this compound was examined in plasma, urine, and feces. The plasma samples were collected for 24hr, urinary and fecal samples for 72hr. While any peak of CKD-602 in HPLC chromatograms was not detected from plasma and urine it was detected in feces (peaks, 9.8 min). However, additional peak area was about 0.5% of the peak area of parent CKD-602. Therefore, CKD-602 may be eliminated with the parent form and rarely metabolized in the body. 4. After I.v. administration of CKD-602 at 10mg/kg in rats, urinary and fecal excretions were examined for 72hrs post dose period. 87% of total urinary excretion of CKD-602 was excreted within 8hr after administration, 53%, and 32% of total fecal excreted amounts were determined in 0-24 hr and 24-48hr periods, respectively. The total excretion amounts of CKD-602 into urine and feces were 94% of the administered dose.

• 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.

• 한국환경과학회지
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• 제16권2호
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• pp.219-225
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• 2007

Endocrine disrupting compounds (EDC's) are chemicals that either mimic endogenous hormones interfering with pharmacokinetics or act by other mechanisms. Some endocrine disrupters were reported to be chemical substances that cause apoptosis in cells. A number of reports have indicated that 1,3-DCP, one of the EDC's may act as an endocrine disrupter and also has possible carcinogenic effects. 1,3-DCP, present in commercial protein hydrolysates used for human nutrition, are genotoxic and 1,3-dichloro-2-propanol induced tumors in rats. In the present study, it was investigated whether 1,3-DCP induces ROS generation and apotosis in A549 adenocarcinoma cells. Here we show that 1,3-DCP inhibits the growth of lung cancer cell lines and generates reactive oxygen species (ROS), a major cause of DNA damage and genetic instability, It was investigated that 1,3-DCP increases G1 phase cells after 12 hours, thereafter abruptly draws A549 cells to G0 state after 24 hours by flow cytometric analysis. 1,3-DCP induces p53 and $p21^{Cip1/WAF1}$ activation time- and dose-dependently by 24 hours, while the level $p21^{Cip1/WAF1}$ was decreased after 48 hours. These results suggest that 1,3-DCP, an EDC's generates ROS and regulates genes involved with cell cycle and apoptosis.

• Journal of Pharmaceutical Investigation
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• 제33권4호
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• pp.319-322
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• 2003

Many studies have been attempted to overcome the problems of paclitaxel related to the extremely low aqueous solubility of paclitaxel and the unexpected side-effects caused by $Cremophor^{\circledR}$ EL in a commercial paclitaxel formulation, $Taxol^{\circledR}$. In order to formulate a new delivery system suitable for intravenous administration without toxic excipients, in this study, paclitaxel was incorporated into solid lipid nanoparticles (Px-SLN) by hot homogenization technique using a microfluidizer. Particle size and zeta potential were measured by a Zetasizer. In vitro drug release experiment was performed by a dialysis diffusion method. Each Px-SLN or $Taxol^{\circledR}$ was intravenously administered to the male Sprague-Dawley rats at a dose of 5 mg/kg as paclitaxel. Blood samples were deproteinated with acetonitrile and assayed for paclitaxel by the validated HPLC/MS/MS method. Mean particle size and zeta potential were measured as 72.1 nm (< Polydispersity 0.3) and -41.5 mV, respectively. The content of paclitaxel in SLN was 1.42 mg/ml and the drug loading efficiency was $71.2{\pm}4.3%$. The $AUC_t$ of Px-SLN was 3.4-fold greater than that of $Taxol^{\circledR}$. The Px-SLN might be a promising candidate for an alternative formulation for the parenteral delivery of paclitaxel.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.228-228
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• 1996

1, 흰쥐에서 IPM 단독투여시보다 DHP-I 저해제인 CS와의 병용투여시 AUC가 4배 이상, t$_{1}$2/가 약 3배 증가하였으며 MEPM의 경우는 AUC가 5배 이상, t$_{1}$2/가 약 1.8배 증가하였다. 2. Guinea pig에서 IPM 단독투여시보다 CS와의 병용투여시 AUC가 약 2.5배, t$_{1}$2/가 약 1.4배 증가하였으며 MEPM의 경우는 AUC, t$_{1}$2/ 모두 거의 변함이 없었다. 3. 위의 결과 흰쥐에서 IPM과 MEPM에 대한 CS의 영향이 매우 큰 것으로 나타났으며 따라서 약물동력학적인 파라메타에도 커다란 변화를 주었다. 반대로 Guinea Pig에서는 CS의 병용투여로 IPM의 AUC에만 변동을 주었을 뿐 t$_{l}$ 2/에는 크게 영향을 미치지 않았고 MEPM의 체내동태에는 거의 영향을 미치지 않았다. 4. Guinea pig에서 전체 투여량에 대한 MEPM의 요중회수율은 66.58$\pm$3.44%이었고 IPM의 경우는 7.00$\pm$0.95%이었다. 그러나 DHP-I 저해제인 CS와의 병용투여시 IPM의 요중회수율이 57.77$\pm$11.46%로 증가하여 MEPM과 거의 비슷한 양상을 나타냈다. 이는 guinea pig에서 DHP-I에 의한 IPM의 대사가 CS에 의해 차단됨을 시사하는 것이라고 사료되며 guinea pig에 존재하는 DHP-I은 MEPM보다 IPM에 대해 더 높은 친화도를 갖는 것으로 사료된다. 5. Carbapenem계 항생제의 약물동력학적 스크리닝을 위한 소동물로는 흰쥐보다도 guinea pig가 적합한 것으로 생각되나 동물종차에 의한 약물동력학적 연구 및 DHP-I의 활성에 대한 연구가 더 면밀히 이루어져야 할 것으로 생각되며 BO-2727, panipenem, biapenem 등 다른 carbapenem 항생제에 대한 광범위한 약물동력학적 연구가 진행되어 새로운 carbapenem계 항생제 개발에 따른 인체내 거동을 예측할 수 있는 치적의 실험동물모델이 확립되어야 할 것이다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.243-243
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• 1996

백금착물 항암제 후보물질로서 합성된 KBP31705-Cl27, KBP30603-901을 기존 화합물인 cisplatin 및 carboplatin과 pharmacokinetic profile을 비교 검토하였다. 웅성 Sprague-Dawley rat을 sodium pentobarbital 마취하에서 방광 및 대퇴동맥과 정맥에 polyethylene tubing을 사용하여 catheterization시켰다. Urine 배출이 안정화되었을 때 대퇴정맥내로 cisplatin과 KBP31705-Cl27은 2 mg/kg, carboplatin과 KBP 30603-901은 20mg/kg 용량으로 주사한 후 2, 4, 6, 8, 10, 15, 20, 30, 45, 60, 120 분에 대퇴동맥으로부터 혈액을 채취하였으며 urine은 약물투여 후 1시간 간격으로 4시간동안 채취하였다. Plasma와 urine중의 platinum농도는 inductively coupled plasma-mass spectrometer를 사용하여 측정하였고, pharmacokinetic parameters는 non-linear least square computer Program인 PCNONLIN을 이용하여 산출되었다. 혈중 platinum농도와 시간의 관계에서 KBP31705-Cl27은 cisplatin과 비교하여 alpha-phase에서 혈중 농도는 낮지만 비슷한 양상을 나타내었고, beta-phase에서는 비교적 느리게 소실됨을 보였다. Urine으로 4시간동안 배출된 platinum양은 각각 투여량의 52, 56%로서 두 약물에서 비슷하였다. 또한 KBP30603-901은 carboplatin과 비교하여 alpha-phase는 거의 비슷한 패턴을 나타내었으나, beta-phase는 훨씬 느리게 감소하여 반감기가 길다는 것을 보여 주었으며 또한 이것은 urine으로 4시간동안 배출된 platinum양이 KBP30603-901의 경우 투여량의 46%로서 carboplatin의 59%보다 적게 배출된다는 data와도 일관됨을 보여주었다. 이상의 결과로 볼 때 KBP30603-901이 다른 백금착물 항암제보다 체내에 머무르는 시간이 길어 혈중에서 보다 오랜 시간동안 머물러 높은 유효농도를 유지할 수 있을 것으로 사료된다.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.15-21
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• 2010

Sibutramine is an orally administered centrally-acting antiobesity agent and inhibits both noradrenaline(norephinephirine) and serotonin(5-HT) reuptake. These effects are contributed by its active metabolites, M1 and M2. However, as the free base form of sibutramine is an oil form in room temperature, it had the problem of handling and stability. Thus, this drug should be used in the form of acid salt form in the pharmaceutical application. Unfortunately, anhydrous sibutramine hydrochloride is highly hygroscopic and unstable. In order to solve the hygroscopicity of the anhydrous salt form, another sibutramine acid salt form must be developed as a hydrate form. In this study. to overcome these problems, various of sibutramine acid salt forms were prepared with the pharmaceutically available salts such as maleate, esylate, mandelate, camsylate, besylate, salicylate, tartrate, isethionate and malate forms, and their physicochemical properties were investigated. Sibutramine malate was selected for excellent solubility and stability among the listed salt forms above. Its pharmacokinetic parameters were evaluated in rats comparing with sibutramine HCl, resulting in similar parameters. In vitro dissolution study of sibutramine malate-loaded capsule was performed comparison with commercial product ($Reductil^{(R)}$) in pH 1.2, pH 4.0, pH 6.8 and water medium. Our results indicated that there were no significant differences in their dissolution profiles were similar in all tested medium. Thus, sibutramine malate-loaded capsule should be a potential candiate due to its excellent solubility, good stability and biosimilar absorption.

• Bulletin of the Korean Chemical Society
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• 제35권11호
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• pp.3188-3194
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• 2014

Compound K (CK) was formulated as polymeric micelles (PM) using Pluronic$^{(R)}$ F-127 to enhance the oral absorption of CK, an intestinal bacterial metabolite of ginseng protopanaxadiol saponin. The physicochemical properties of Ck-loaded PM were characterized and an in vitro transport study using the Caco-2 cell system as well as an in vivo pharmacokinetic study using SD rats was carried out. The hydrodynamic mean particle size of CK-loaded PM (CK-PM) was $254{\pm}23.45nm$ after rehydration and the drug loading efficiency was ca. 99.9%. The FT-IR spectroscopy, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy data supported the presence of a new solid phase in the PM. The $P_{app}$ value of in vitro Caco-2 cell permeation of CK-PM and the oral absorption of CK was enhanced about 1.2-fold and 2.6-fold compared to CK suspension, respectively, showing that the present PM formulation enabled an enhancement of oral CK absorption.

• Biomolecules & Therapeutics
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• 제10권1호
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• pp.37-42
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• 2002

Brain drug targeting through the blood-brain barrier (BBB) in vivo is possible with peptidornirnetic monoclonal antibodies that undergo receptor-mediated transcytosis through the BBB. Monoclonal antibody to the rat transferrin receptor, such as the OX26 was studied in rats as a transport vector through BBB on the transferrin receptor. But, OX26 is not an effective brain delivery vector in mouse. In the present studies, rat monoclonal antibody, 8D3 to the mouse transferrin receptor were evaluated for brain drug targeting vector intransgenic mouse model. Pharrnacokinetic parameters in plasma and organ uptakes were determined at varioustimes after i.v. bolus injection of [$^{}125}I$] 8D3 in Balb/c mice. Brain uptake of [$^{}125}I$] 8D3 was also studied with an internal carotid artery perfusioncapillary depletion method. After i.v. injection of [$^{}125}I$] 8D3, plasma concentrations declined biexponentially with elimination half lift of approximately 2.2 hours. Brain uptake of [$^{}125}I$] 8D3 was $0.50{\pm}0.09$ persent of injected dose per g brain after 2 hours i.v. injection. After perfusion 5 min the apparent volume of distibution of [$^{}125}I$] 8D3 in brain was $22.3 {\mu}l/g,$ which was 4.8 fold higher than the intravascular volume. These studies indicate rat monoclonal antibody to the mouse transferrin receptor, 8D3 may be used for brain drug targeting vector in mice.

• 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.