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박정란,강진형,구효정,노지영,류형철,박상욱,고동현,조일환,이주영,황다니엘,김인경 한국약제학회 2003 Journal of Pharmaceutical Investigation Vol.33 No.2
Selective COX (cyclooxygenase)-2 inhibitors including celecoxib have been shown to induce apoptosis and cell cycle changes in various tumor cells. New inhibitors are recently being developed as chemomodulating agents. We evaluated celecoxib and screened 150 synthetic compounds for anti-proliferative activities in vitro. Effects of celecoxib on COX activity, cell growth, cell cycle distribution, and apoptosis induction were determined in A549 COX-2 overexpressing human non-small cell lung cancer (NSCLC) cells. The COX inhibition of celecoxib increased with concentration up to 82% at 1μM after 24 hr exposure. Forty μM and 50μM of celecoxib induce G_1 arrest, and TUNEL-positive apoptotic cells, respectively. Among 150 compounds, several compounds were selected for having greater COX-2 inhibitory activity and higher selectivity than celecoxib with growth inhibitory activity. Celecoxib showed concentration-dependent COX inhibitory activity, and ability to induce cell cycle arrest and apoptosis in human NSCLC cells in vitro. Among synthetic analogues screened, several compounds showed promising in vitro activity as COX-2 inhibitory anticancer agents, which warrant further evaluation in vitro and in vivo.
항고형암제의 활성평가를 위한 in vitro 삼차원 암세포 배양계의 확립
이상학,이주호,구효정 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.5
For the efficient determination of activity against solid tumors, an in vitro tumor model that resembles the condition of in vivo solid tumors, is required. The purpose of this study was to establish a rapid culture method and viability assay for an in vitro 3-dimensional tumor model, multicellular spheroid (MCS). Among 12 human cancer cell lines, a few cell lines including DUD-1 (human colorectal carcinoma cells) formed fully compact MCS which was adequate for in vitro viability assay. DLD-1 MCS showed steady growth reaching 700 pm diameter after 11 day culture. DUD-1 cells grown as MCS showed significant increase in G_(0)/G₁ phase compared to the monolayer cells (73.9% vs 45.7%). but necrotic regions or apoptotic cells were not observed. The cells cultured as MCS showed resistance to 5-FU (10.3 fold higher IC_(50)) compared to monolayers. however, tirapazamine (a hypotoxin) showed similar activity in both culture systems. In summary, MCS may be a valid in vitro model for activity screening of anticancer agents against human solid tumors and also exploitable for studying molecular markers of drug resistance in human solid tumors.
흰쥐 생체시료 중 5-플루오로우라실 및 테가푸르의 안정성
장지현,박종국,강진형,정석재,심창구,구효정 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.3
5-Fluorouracil (5-FU) is an antimetabolite anticancer agent active against many types of solid tumors. Tegafur (TF), a prodrug of 5-FU, is frequently used in combination with uracil as dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine. We studied the stability of 5-FU and TF in biological fluids of rats and determined their bioavailability (BA) and excretion into bile, and urine. The drug concentrations were analyzed by an HPLC method. At room temperature, there was a 14-30% decrease in the concentration of 5-FU and TF in bile, urine, and plasma specimen at 10 and 100 μg/ml over 240 min. No significant difference was noted among the sample types or between two different concentrations of 10 and 100 μg/ml. The decrease in drug concentration was significantly less in samples kept on ice (6-12%) for both drugs. These data indicate that biological fluid samples containing 5-FU or TF in plasma, urine, or bile should be placed on ice during the sample collection. Following these storage guidelines, samples were collected after administration 50 ㎎/㎏ of each drug via i.v. or oral route. BA was 1.5 folds greater for TF (60%) than that of 5-FU (42%). Approximately 0.52 and 3.3% of the i.v. doses of 5-FU and TF was excreted into bile, respectively. Renal clearance of 5-FU was about 16% of its total body clearance. These results suggest that instability of 5-FU and TF in biological fluids should be considered in pharmacokinetic or pharmacogenomic studies.
테오필린과 그 대사체의 HPLC 동시 정량 및 신(腎) 배설 특성
구효정,심창구,이민화,김신근,Kuh, Hyo-Jeong,Shim, Chang-Koo,Lee, Min-Hwa,Kim, Shin-Keun 한국약제학회 1991 Journal of Pharmaceutical Investigation Vol.21 No.1
A high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of theophylline(TP) and its metabolites, 1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU), in rat plasma and urine. An $100\;{\mu}l$ aliquot of a plasma or urine sample was mixed with $250\;{\mu}l$ of acetonitrite and vortexed. After centrifugation, $200\;{\mu}l$ (plasma) or $20\;{\mu}l$ (urine) aliquot of the supernatant was dried by $N_2$ stream and redissolved in $100\;{\mu}l$ (plasma) or $200\;{\mu}l$ (urine) of the mobile phase. A $20\;{\mu}l$ of the mobile phase solution was injected onto a $C_{18}$ reversed-phase column. The column was maintained at $45^{\circ}C$ by the aid of electric heating jacket. The mobile phase was a 3%(v/v) methanol solution in deionized water which contains sodium acetate (100 mM) and tetrabutyl ammonium hydroxide (4 mM). pH of the mobile phase was adjusted 4.5 by the addition of acetic acid. Detection limits for TP, 1-MU, and 1,3-DMU in plasma were 0.2, 0.1 and $0.1\;{\mu}/ml$, respectively and the corresponding values in urine were all $5\;{\mu}g/ml$. Inter- and intra-day variability of the assay for all compounds in the plasma samples was less than 5.5 and 3.8%, respectively. The retention times for 1-MU, 1,3-DMU, and TP were approximately 7, 8.5 and 18 min, respectively. Sample preparation procedure used in this method was simple, rapid and reproducible. Renal clearance of TP and its metabolites in rats showed plasma concentration dependency indicating renal tubular secretion and reabsorption of them.
Pharmacokinetics of Primaquine and Carboxyprimaquine in Korean Patients with Vivax Malaria
Yang-Ree Kim,Hyo-Jeong Kuh,Mi-Young Kim,Yo-Sook Kim,Woo-Chul Chung,Sang-Il Kim,Moon-Won Kang 대한약학회 2004 Archives of Pharmacal Research Vol.27 No.5
Primaquine is used for relapses caused by vivax malaria hypnozoites. No studies on the pharmacokinetics of primaquine (PMQ) has been reported in Korean patients. In our study, thirty vivax malaria patients were given 15 mg primaquine daily for 14 days after 3 days of chloroquine treatment. Plasma samples were taken at intervals after each daily dose of PMQ for 3 days. Plasma concentrations of PMQ and carboxyprimaquine (CPMQ), the major metabolite of primaquine, were measured by HPLC. The PMQ concentrations reached a maximum of 0.28±0.18 mg/mL at 1.5 h after the first dose. The maximum concentration of CPMQ was 0.32±0.13 mg/mL at 4 h. Higher drug concentrations with repeated dosing were observed for CPMQ, but not for the parent drug, PMQ. The elimination half-life was 3.76±1.8 h and 15.7±12.2 h, for PMQ and CPMQ, respectively. Large variation in the plasma concentrations of both drugs was observed. Overall, PMQ is absorbed and metabolized rapidly after oral administration. It was noted that the mean peak plasma concentration of PMQ was significantly higher and that of CPMQ was lower in our patients compared to other studies. This suggests a potential difference of inter-ethnic groups, which warrants further investigations.
Pharmacokinetics of Primaquine and Carboxyprimaquine in Korean Patients with Vivax Malaria
Kim, Yang-Ree,Kuh, Hyo-Jeong,Kim, Mi-Young,Kim, Yo-Sook,Chung, Woo-Chul,Kim, Sang-Il,Kang, Moon-Won The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.5
Primaquine is used for relapses caused by vivax malaria hypnozoites. No studies on the pharmacokinetics of primaquine (PMQ) has been reported in Korean patients. In our study, thirty vivax malaria patients were given 15 mg primaquine daily for 14 days after 3 days of chloroquine treatment. Plasma samples were taken at intervals after each daily dose of PMQ for 3 days. Plasma concentrations of PMQ and carboxyprimaquine (CPMQ), the major metabolite of primaquine, were measured by HPLC. The PMQ concentrations reached a maximum of 0.28$\pm$0.18 $\mu\textrm{g}$/mL at 1.5 h after the first dose. The maximum concentration of CPMQ was 0.32$\pm$0.13 $\mu\textrm{g}$/mL at 4 h. Higher drug concentrations with repeated dosing were observed for CPMQ, but not for the parent drug, PMQ. The elimination half-life was 3.76$\pm$1.8 hand 15.7$\pm$12.2 h, for PMQ and CPMQ, respectively. Large variation in the plasma concentrations of both drugs was observed. Overall, PMQ is absorbed and metabolized rapidly after oral administration. It was noted that the mean peak plasma concentration of PMQ was significantly higher and that of CPMQ was lower in our patients compared to other studies. This suggests a potential difference of inter-ethnic groups, which warrants further investigations.