• Journal of Pharmaceutical Investigation
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• 제31권2호
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• pp.113-117
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• 2001

CKD602, a camptothecin derivative, is a synthetic and water-soluble anticancer agent possessing of topoisomerase I inhibiting activity. DPPC and DSPE-PEG liposomal formulations entrapped with CKD602 were developed. DSPE-PEG liposome, or PEGylated liposome, encapsulating CKD602 composed of dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearoyl-N-monoethoxy poly (ethyleneglycol) succinylphosphatidylethanolamine $(DSPE-PEG_{2000})$ (22:11:2) was prepared by reverse-phase evaporation method. Formed liposomes were characterized in terms of the morphology, size and encapsulation efficiency. To elucidate the in vitro stability, PEGylated liposome was incubated in human plasma, and the adsorbed proteins onto the surface of liposomes were applied to the SDS-PAGE. In vitro cytotoxicity of CKD602 encapsulated in PEGylated liposome was studied in human cervical cancer cell line (HeLa). CKD602 in PEGylated liposome was found to be 40-fold more effective $(IC_{50}=1\;nM)$ than free CKD602 $(IC_{50}=40\;nM)$ in inhibiting the growth of HeLa cells in vitro.

• Journal of Pharmaceutical Investigation
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• 제32권2호
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• pp.81-85
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• 2002

Three polymorphic modifications of CKD-602, water soluble derivative of camptothecin, were obtained by the recrystallization from different organic solvents and characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and X-ray powder diffraction (XRPD). The major endothermic peaks of the DSC curve of Form 1, Form 2 and Form 3 was shown at $268.71^{\circ}C$, $247.83^{\circ}C$, $244.76^{\circ}C$, respectively. Form 2 was elucidated to be an acetic acid solvate and Form 3 was elucidated to be a methanol solvate. The dissolution patterns of these three modifications were also checked in distilled water at $37{\pm}0.5^{\circ}C$, for 30 minutes. The polymorphic modifications showed differences in the dissolution rate. The dissolution rate of Form 1 was faster than that of other polymorphic modifications. When stored at different relative humidity over the period of 3 months, all of the polymorphic modifications did not undergo transformation.

• 대한약학회:학술대회논문집
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• 대한약학회 2001년도 Proceedings of the Pharmaceutical Society of Korea
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• pp.226.2-227
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• 2001

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.66-69
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• 2000

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 NEW STRATEGY FOR DRUG DEVELOPMENT IN POST-GENOMIC ERA(대한약학회)
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• pp.262.2-262.2
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• 2000

• 약학회지
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• 제42권4호
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• pp.431-436
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• 1998

The pharmacokinetics of CKD-602, a new camptothecin anticancer derivative, were studied in mice, rats and dogs following a single or multiple intravenous administration, and the following results were obtained. The blood levels of CKD-602 declined in biphasic fashions with peak plasma levels $(C_0)$ of $2.63{\mu}g/ml$ in mice, $2.27{\mu}g/ml$ in tumor bearing mice, $2.84{\mu}g/ml$ in rats at a dose of 20mg/kg, and of 0.02mcg/ml in dogs at a dose of 0.5mg/kg. The plasma half-lives $(t_{1/2}{\beta})$ were 9.55hr in mice, 9.94hr in tumor bearing mice, 9.98hr in rats and 12.75hr in dogs. AUC of CKD-602 was increased linearly with the dose at a range from 5 to 20mg/kg. Moreover, Cltot and Vdss were also not significantly changed with increasing the dose. On the other hand, after 5 daily intravenous bolus injection of CKD-602 (5mg/kg) in rats, $t_{1/2}{\beta}$, AUC and MRT of CKD-602 were 11.90hr, $3.19{\mu}g{\cdot}hr/ml$, and 11.61hr, respectively, which were slightly higher than after the single bolus injection.

• 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.

• 약학회지
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• 제49권5호
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• pp.428-436
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• 2005

DNA topoisomerase I(TOP1) helps the control of DNA replication, transcription and recombination by assist­ing breaking and rejoining of DNA double strand. Camptothecin (CPT) and its derivative, topotecan, are known to inhibit TOP1 by intercalating into TOP1-DNA complex. Recently various non-CPT intercalators are synthesized for a new class of TOP1 inhibitors. In this study, six compounds isolated from Poria cocos were investigated for their interaction with TOP1­DNA complex using the flexible docking program, FlexiDock. The binding modes were analyzed and compared with the TOP1 inhibition activities. The compounds that showed potent activity were intercalated between the + 1/-1 base pairs of DNA, located near the active site phosphotyrosine723 and formed hydrogen bonds with active site residues. On the other hand, compounds with no activity were not docked at all. The binding modes were well correlated with the inhibition activity, suggesting the possibility that potent inhibitors can be designed from the information presented by the docking study.

• Tuberculosis and Respiratory Diseases
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• 제66권2호
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• pp.93-97
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• 2009

연구배경: Belotecan (Camtobell, CKD-602, Chongkundang Pharm., Korea)은 camptothecin의 치환체로 topoisomerase I 효소를 억제하여 항암효과를 나타내는 것으로 알려져 있다. 이에 2차 항암화학요법에 치료제로써 Belotecan 의 효과, 생존율 및 부작용에 대해 연구하였다. 방 법: 이에 소세포폐암에서 etoposide와 platinum을 사용한 1차 항암화학요법에서 실패한 49명의 환자들을 대상으로 2차 항암화학요법에 Belotecan을 투약하였다. 결 과: 전체 반응률은 25%였으며, 11명의 환자에서 partial response를 보였다. 또한 1차 항암화학요법 이후 90일 이내에 재발한 군과 90일 이상 경과한 군간에 유의한 차이는 보이지 않았다. 전체 환자의 중심생존기간은 10.3개월(290일)이었고, 비반응군에서는 186일(95% CI; 67-305)로 반응군의 471일(95% CI; 234-568)에 비해 생존기간의 감소 유의하게 있음을 확인하였다(p=0.07). 결 론: 2차 항암화학요법의 치료제로써 Belotecan의 효능과 부작용에 대해서는 향후 무작위 비교 연구가 필요할 것으로 사료된다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
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• pp.71-71
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• 1993

Carboxylesterase is widely distributed in the tissues of vertebrates, insects, plants and mycobacteria. Among various tissues of animals and humans, the highest esterase activity with various substrates is found in the liver. Kidney has moderate carboxylesterase activity in the proximal tubules. Considerable esterase activity is also found in the small intestine epithet elial cells and serum of mammals. Besides these tissues, carboxylesterase has been found in the lung, testis, adipose tissue, nasal mucosa and even in the central nervous system. Hepatic microsomal carboxylesterase catalyzes the hydrolysis of a wide variety of endogenous and exogenous compounds such as carboxylester, thioester and aromatic amide. Since carboxylesterases are important for metabolic activation of prodrugs and detoxification of xenobiotics, differences in substrate specificity and immunological properties of this enzyme are important in connection with choosing a suitable laboratory animal for the evaluation of biotransformation and toxicity of drugs. On the other hand, liver, kidney, intestine and serum were found to contain multiple forms of carboxylesterases in animal species and humans. In fact, we have purified more than fifteen isoforms of carboxylesterases from microsomes of liver, kidney and intestinal mucosa of nine animal species and humans. and characteristics of these isoforms were compared each other in terms of their physical and immunochemical properties. On the other hand, we have reported that hepatic microsomal carboxylesterases are induced by many exogenous compounds such as phenobarbital, polycyclic aromatic hydrocarbons, Aroclor 1254, aminopyrine and clofibrate. Later, we showed that some isoforms of hepatic carboxylesterase were induced by glucocorticoids such as dexamethasone and 16 ${\alpha}$-carbonitrile, but other isoforms were rather inhibited by these compounds. These findings indicate that involvement of carboxylesterases in the metabolism and toxicity of drugs should be explained by the isoforms involved. Since 1991, we have carried out detailed research investigating the types of carboxylesterases involved in the metabolic activation of CPT-11, a derivative of camptothecin, to the active metabolite, SN-38. The results obtained strongly suggest that some isoforms of carboxylesterase of liver microsomes and intestinal mucosal membrane are exclusively involved in CPT-11 metabolism. In this symposium, the properties of carboxylesterase isoforms purified from liver, kidney and intestine of animal species and humans are outlined. In addition, metabolism of CPT-11, a novel antitumor agent, by carboxylesterases in relation to the effectiveness will also be discussed.