• Journal of Pharmaceutical Investigation
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• v.18 no.3
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• pp.139-144
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• 1988

Piperacillin phthalidyl ester was synthesized by reacting piperacillin with triethylamine and bromophthalide in acetone and its chemical structure was determined by UV, IR, and PMR. The partition coefficient of the ester was increased and the ester was more lipophilic and less water soluble than piperacillin. The ester did not show the antimicrobial activity against Bacillus subtilis ATCC 6633 in vitro, but when hydrolyzed, the parent drug of ester, piperacillin, revealed antimicrobial activity in vivo. After a single oral dose of both piperacillin and the ester to rabbits, the serum piperacillin concentration was measured by bioassay. The ester exhibited improved pharmatokinetic characteristics: $T_{max}\;of\;2hr,\;C_{max}\;of\;4.26{\mu}g{\cdot}ml^{-1},K_{el}\;of\;0.057hr^{-1},\;and\;total\;AUC\;of\;85.42{\mu}g{\cdot}hr{\cdot}ml^{-1}$. Piperacillin on the other hand, did not exhibit any gastro-intestinal absorption.

• Archives of Pharmacal Research
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• v.27 no.8
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• pp.878-883
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• 2004

Tacrolimus (FK506), which is isolated from Streptomyces tsukubaensis, is a new potent immu-nosuppressant. Because of poor solubility in water, the conventional intravenous dosage forms of tacrolimus contain surfactants such as cremophor EL (BASF Wyandotte Co.) or hydroge-nated polyoxy 60 castor oil (HCO-60) which may cause adverse effects. This study relates to a polymer-tacrolimus conjugate, which can be dissolved in water, formed by chemically binding the sparingly soluble drug, tacrolimus, with the water soluble polymer, methoxypoly(ethylene glycol) (mPEG). Water soluble tacrolimus-mPEG conjugates have been synthesized and shown to be function in vitro as prodrugs. These conjugates are in the form of an ester wherein the 24-, 32- or 24,32-positions are esterified. The desired 24-, 32- or 24,32-esterified com-pounds were obtained by initially acylating of tacrolimus with iodoacetic acid at the 24-,32-, or 24,32-positions and then reacting the resulting acylated tacrolimus with a mPEG in the pres-ence of a base such as sodium bicarbonate. These conjugates were converted again into tac-rolimus by the action of enzymes in human liver homogenate, and the half-lives of the conjugates are approximately 10 min in the homogenate, indicating that the esterified tacroli-mus derivatives may be practically applicable as a prod rug for the immunosuppressant.

• YAKHAK HOEJI
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• v.34 no.6
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• pp.395-400
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• 1990

The FU-fat conjugates(4a-e) as a prodrug have been synthesized by condensing various fatty acids(1a-e) via isocyanates(2a-e) as carbamoyl group at $N^1-position$ of 5-fluorouracil and their structures characterized. Preliminary testing for their antitumor effect was carried out on leukemia L1210 cells in culture. Most of them(4a-d) like the parent FU exhibited less than 50% inhibition on grouth of the cultrued cells at the concentration of $1\;{\times\;10^{-7}M$. Only a dicarboxylic acid derivative, 4e, showed over 50% inhibition at the same level.

• Natural Product Sciences
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• v.7 no.3
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• pp.63-67
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• 2001

${\beta}-Glucuronidase-inhibitory$ and hepatoprotective effects of Chungpesagan-tang, which has been used for liver diseases and stroke, on $CCl_4-induced$ hepatotoxicity of rats was investigated. Chungpesagan-tang potently inhibited ${\beta}-glucuronidases$. Serum AST, ALT and LDH levels of the $CCl_4$ group orally treated with Chungpesagan-tang (100 mg/kg) were lowered to 47, 28 and 58% of the $CCl_4-treated$ group, respectively. Among the ingredients of Chungpesagan-tang, Puerariae Radix, Scutellariae Radix and Rhei Rhizoma potently inhibited the ${\beta}-glucuronidase$ and protected $CCl_4-induced$ liver injury. The hepatoprotective activity of Puerariae Radix was affected by ingredients of Chungpesagan-tang: Scutellariae Radix had the synergistic activity, but Angelicae Tenussimae Radix exhibited the antagonistic activity. These results suggest that the ${\beta}-glucuronidase$ inhibitor of herbal medicines may protect $CCl_4-induced$ liver injury and puerarin should be a natural prodrug for the hepatoprotective effect.

• Biomolecules & Therapeutics
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• v.14 no.3
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• pp.148-151
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• 2006

We have previously reported that 2.4 kb of L-plastin promoter (LP) could regulate the expression of adenoviral vector (AV) exogenous genes in a tumor cell specific manner. In the present study, we tested if the replication competent AdLPE1A vector results in a direct cytotoxic effect in hepatocelluar carcinoma (HCC) cells. In vitro cytotoxicity tests were carried out with replication-competent (AdLPE1A) and -incompetent (AdLPCD) LP-driven vectors. AdLPE1A is an AV in which LP was inserted 5' to the E1A and E1B genes. The AdLPCD vector contains LP and the E. coli cytosine deaminase (CD) gene in transcription unit. Exposure of cells to AdLPE1A generated a significant cytotoxic effect as compared to the control. Almost 90% of the cell had manifested the characteristic cytopatic effect on day 9 after infection of cells with 10 MOI of AdLPE1A. On the other hand, almost 35% of the cells were left when the cells had been treated with 100 MOI of AdLPCD together with 5-FC on day 9 when compared with the cells which had never been exposed neither 5-FC nor AdLPCD. These results showed that the replication competent AdLPE1A vector could kill the HepG2 cells directly by the oncolytic effect of the virus. The replication competent AV vector carrying viral E1A generated greater cytotoxic effect than the replication incompetent AV, which contains the CD prodrug activation transcription unit without E1A, in HepG2 cells.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.11a
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• pp.99-104
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• 1994

Renin-Angiotensin계는 정상 및 질병시의 혈압조절에 매우 중요한 역할을 담당하고 있음이 밝혀지면서, 이 조절계의 특정단계를 간섭함으로써 새로운 고혈압치료제를 개발하려는 연구가 일찍부터 시도되었다. (그림 1). 그 중에서 내인성 생리활성물질인 Angiotensin II의 합성을 차단하는 ACE 저해제는 임상적으로 고혈압 및 심부전치료제로서 유용성이 인정되어 현재 널리 사용되고 있다. ACE 저해제는 종종 마른기침, 발적과 같은 부작용이 나타나므로 이러한 부작용을 극복하려는 연구가 많이 있었으나 이는 작용기전에서 기인되는 것으로 해결에 한계를 보여왔다. 그런데 1982년 일본의 Takeda사의 연구진은 S-8307, 8308이라는 효과가 매우 약하기는 하지만 Angiotensin II 수용체를 선택적으로 차단하는 비펩타이드성의 AII길항물질을 특허 출원하였다. 미국의 Du Pont사는 AII길항약물이 효능은 그대로 유지하면서 ACE 저해제들의 부작용을 해결할 수 있을 것으로 예상하고 Takeda 화합물을 모핵으로하여, 많은 유도체들을 합성하면서 구조-활성 연구를 수행한 결과 비펩타이드성길항제인 Dup 753(Losartan, Cozaar$^{R}$) (2-N-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazole-5-yl)biphenyl-4-yl) imidazole, potassium salt)을 발견하게 되었다. 이 Dup 753은 특별히 AII수용체중 혈압조절과 관련이 있는 AT1 수용체를 선택적으로 차단하는데, 효력은 ACE 저해제인 captopril과 유사하며, 경구흡수가 잘되고 지속시간이 길어 하루에 한번 먹는 경구제제로 개발되고 있는 것으로 알려져 있다. 이 Dup 753의 지속시간이 긴 것은 그 대사물인 Exp 3174에 기인하는 것으로 알려져 있으며, 대사체가 Dup 753에 비해 효력도 훨씬 더 높고 지속시간도 길어서, Dup 753은 일종의 prodrug적 개념이 들어있는 약물이라 할 수 있다.

• Journal of Food Hygiene and Safety
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• v.12 no.3
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• pp.228-233
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• 1997

Drug Dclivcry system (DDS) purpose to getting better remedial result by improving medication from ordinary methods. Applied for DDS, to improve selectivity and comtinuity during absorbing and delivery step, polmer drug (prodrug) was prepared by the esterification with dextran in such of biodegradable polymer and phthalylsulfathiazole with is efficient for entilitis. The polymer durg was prepared with dextran and phthalylsulfathiazole by the esterification. The synthetic procedures of polymer drug was performed by acid chloride and DCC methods. Polymer drug was synthesized in high yield by acid chloride method than DCC method. The antibiotic activities of polymer drug exhibited growth-inhibitory activity against Staphylococcus aureus, Staphylococcus epidermidis, E. coli, Salmonella typhimurium, Klebsiella pneumoniae at the concentration of 500 *g/m* in general through in vitro. As a result of test, polymer drug has 1/2 MIC than phthalylsulfathiazole. Also, it has high level MIC as much as phthalylsulfathiazole with Proteus, Pseudomonas. We conducted possibility of DDS as an applied for medicine with synthesized polymer drug by using natrural polymer. We consider that clinical research must be followed to verify safety and efficacy for controlled release, activity and toxicity.

• YAKHAK HOEJI
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• v.55 no.1
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• pp.75-79
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• 2011

The replication competent adenoviral vector (AV), AdLPCDIRESE1A was generated and reported previously to have cytotoxic effects in some cell lines. In AdLPCDIRESE1A, the expression of cytosine deaminse (CD) and E1A genes are under the control of tumor-specific L-plastin promoter. CD enzyme can deaminate the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic 5-fluorouracil (5-FU). E1A gene is essential for viral replication. Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. Thus, we have conducted in vitro preclinical study to evaluate effectiveness of AdLPCDIRESE1A on HCC. The efficacy of cytotoxicity was measured by generation of cytopathic effect (CPE) and cell counting. We infected HepG2 cells with various MOI of vector alone or concurrent with 5-FC. Exposure of cells to AdLPCDIRESE1A generated a significant cytotoxic effect as compared to the control. Almost 83% of the cell had manifested the characteristic cytotoxic effect on day 9 after infection of cells with 10 MOI of vector. We also observed the additive cytotoxic effects when AdLPCDIRESE1A vector had been coadministrated with 5-FC. The results suggest that the use of AdLPCDIRESE1A/5FC may be value in treatment of liver cancer. Further animal studies are needed for clinical trial.

• Korean Journal of Clinical Pharmacy
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• v.20 no.1
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• pp.50-55
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• 2010

Cefetamet pivoxil is a prodrug of cefetamet possessing a broad spectrum of activity against many aerobic gram-positive and -negative organisms. Although many literatures in abroad had introduced its pharmacokinetics about two decays ago, no data have been revealed in Korean subjects. Therefore, this study was aimed to investigate the pharmacokinetics of cefetamet following a single oral administration of cefetamet pivoxil in Korean healthy volunteers. After an overnight fast, a tablet of cefetamet pivoxil (500 mg) was given to eight volunteers, and blood samples were serially taken up to 12 h. Plasma concentrations of cefetamet were determined by HPLC with UV detection. Cefetamet reached the peak concentration ($2.0{\pm}1.3\;{\mu}g/ml$) at $3.0{\pm}0.8$ h, and mono-exponentially decayed at a half-life of $2.6{\pm}0.9$ h. Three volunteers represented very low systemic exposure compared to the others, which provided very large inter-individual variation in Cmax, and AUC. The present results were discussed and reviewed with the previously published data, and a couple of points are suggested for clinical trials of this drug in Korean subject including bioequivalence study.

• Archives of Pharmacal Research
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• v.25 no.4
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• pp.528-533
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• 2002

To evaluate the antithrombotic and antiallergic properties of rhaponticin extracted from Rhei Rhizoma, the in vitro and ex vivo inhibitory activities of rhaponticin and its metabolite, rhapontigenin, were measured. These compounds inhibited in vitro ADP- and collagen-induced platelet aggregation. Rhapontigenin was more potent, with $IC_{50}$ values of 4 and $70{\;}{\mu}g/ml$, respectively. In ex vivo ADP- and collagen-induced rat platelet aggregation, these compounds also exhibited a potent inhibitory effect. The antiplatelet aggregation effects of rhaponticin and rhapontigenin were more potent than those of aspirin. Rhapontigenin showed significant protection from death due to pulmonary thrombosis in mice. Rhapontigenin also showed the strongest inhibitory activity against $\beta-hexosaminidase$ release induced by DNP-BSA. These compounds inhibited PCA reaction in mice. Rhapontigenin intraperitoneally administered showed the strongest inhibitory activity and significantly inhibited PCA at doses of 25 and 50 mg/kg, with inhibitory activities of 48 and 85%, respectively. The inhibitory activity of orally administered rhaponticin was stronger than that of intraperitoneally administered rhaponticin. These results suggest that rhaponticin, in the rhizome of Rhei Rhizoma, is a prodrug that has extensive antiallergic and antithrombotic properties.