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dc.description.abstract본 연구에서는 P-당단백질 저해제인 실리마린을 파클리탁셀과 병용하여 경구로 투여하였을 때 실리마린이 파클리탁셀의 체내 동태와 생체이용률에 미치는 영향을 알아보고자 하였다. 쥐의 혈장에서 파클리탁셀을 정량하기 위하여 내부표준물질로서 n-hexyl p-hydroxy benzoic acid (30 mg/mL) 25 mL을 혈장 100L에 가하고 추출액 tert-butyl methyl ether 1.6mL를 가하여 한번에 추출하였다. 이를 15분 동안 3000rpm에서 원심 분리한 후 1.4 mL의 유기층을 질소기체 하 40℃에서 30분 동안 증발시켰다. 잔사는 60% 아세토니트릴에 녹여 Capcell-pak C18 컬럼에 주입하였다. 이동상으로서 아세토니트릴과 0.1% 인산 혼합액 (51:49, v/v)을 사용하고 자외선 파장 227 nm에서 검출하였다. 동물실험을 위하여 쥐의 경동맥에 폴리에틸렌 튜브를 연결하여 혈액을 채취하였다. 대조군으로서 파클리탁셀을 2 mg/kg의 용량으로 정맥 투여하였고 25 mg/kg의 용량으로 경구 투여하였다. 실험군으로서 실리마린 10, 20, 30, 및 40 mg/kg를 각각 파클리탁셀 25 mg/kg와 병용하여 경구로 투여하였다. 실리마린 10 mg/kg를 파클리탁셀과 병용하여 경구로 투여하였을 때 대조군에 비해 파클리탁셀의 혈장 중 약물 농도-시간 곡선 하 면적 (AUC_(0-24h))과 최고 혈장 중 농도 (C_(max))가 각각 5배와 3배 유의적으로 증가하였다 (p<0.01). 또한, 모든 실험군에서 실리마린과 파클리탁셀을 병용 경구 투여하였을 때 파클리탁셀의 최고 혈장 중 농도, 혈장 중 약물 농도-시간 곡선 하 면적 및 절대생체이용률이 증가하였다. 그러나, 소실 반감기와 최고 혈장 중 농도에 도달하는 시간은 변하지 않았다. 이 실험의 결과로서 쥐의 혈장에서의 파클리탁셀의 HPLC 분석법이 확립되었음을 성공적으로 검증하였고, 파클리탁셀의 약물동태학적 파라미터들은 P-당단백질 저해제인 실리마린에 의해 영향을 받음을 알 수 있었다. 파클리탁셀의 경구 생체이용률은 실리마린과의 병용투여에 의해 향상될 수 있음을 확인하였다.;The objective of this study was to investigate the effect of silymarin, P-gp inhibitor, on the pharmacokinetics and oral bioavailability of paclitaxel after oral co-administration in rats. For determination of paclitaxel in rat plasma, 25 mL of n-hexyl p-hydroxy benzoic acid (30 mg/mL, I.S.) was first added to 100mL. The mixture was then extracted by one-step liquid-liquid extraction with 1.6 mL of tert-butyl methyl ether. After centrifugation at 3000 rpm for 15 min, 1.4 mL of the organic layer was transferred and evaporated under N₂ gas for 30 min at 40℃. The residue was then dissolved in 70 mL of 60 % acetonitrile in deionized water. An aliquot of the solution (50 mL) of the solution was injected into the HPLC system. The capcell-pak C18 UG120 column (4.6 mm ´ 250 mm, 5mm, Shiseido) was used as an analytical column. The mobile phase consisting of acetonitrile and 0.1% phosphoric acid (51:49, v/v) was run at 1.3 mL/min and the effluent was detected at 227 nm using a UV-detector. For the pharmacokinetic study, the common carotid artery of S.D. male rats was cannulated with polyethylene tubing (PE-60) for blood sampling. Paclitaxel was injected intravenously at a dose of 2 mg/kg or administered orally at a dose of 25 mg/kg to the rats as a control. In four treatment groups, paclitaxel (25 mg/kg) was co-administrated with four different doses with silymarin (10, 20, 30 and 40 mg/kg) orally to rats. After the oral co-administration of paclitaxel with 10 mg/kg of silymarin, compared to control (paclitaxel alone) the mean area under the plasma concentration-time curve from 0hr t0 24hr (AUC_(0-24)) and maximum plasma concentration (C_(max)) of paclitaxel increased by 5 and 3 times respectively (p<0.01). The co-administration of paclitaxel with silymarin resulted in improvements of C_(max), AUC_(0-24), and oral absolute bioavailability of paclitaxel. However the elimination half-life (t_(1/2)) and time required to reach C_(max) (T_(max)) of paclitaxel remained unchanged. In conclusion the HPLC method for the analysis of paclitaxel in rat plasma was successfully validated with specificity, linearity, precision and accuracy in this study. The pharmacokinetic parameters of paclitaxel were significantly affected by silymarin, an inhibitor of p-glycoprotein efflux pump. Oral bioavailability of paclitaxel was enhanced by co-administration of silymarin.-
dc.description.tableofcontentsI.INTRODUCTION = 1 II.MATERIALS AND METHODS = 10 1.Materials = 10 2.Instruments = 11 3.Drug formulation = 11 4.Animal experiments = 12 4.1.Preparation of rats = 12 4.2.Intravenous injection and oral drug administration = 13 5.HPLC analysis = 14 5.1.Preparation of stock and standard solutions = 14 5.2.HPLC conditions = 14 5.3.Sample preparation procedure = 15 6.HPLC validation = 17 6.1.Specificity = 17 6.2.Linearity = 17 6.3.Precision and Accuracy = 17 7.Pharmacokinetic analysis = 19 8.Statistical analysis = 20 III.RESULTS = 21 1.HPLC method validation = 21 1.1.Specificity = 21 1.2.Linearity = 23 1.3.Precision and Accuracy = 24 2.Pharmacokinetics of paclitaxel = 26 IV.DISCUSSION = 39 REFERENCES = 43 국문초록 = 48 감사의 글 = 50-
dc.format.extent1362095 bytes-
dc.publisher이화여자대학교 대학원-
dc.titleIncreased Oral Bioavailability of Paclitaxel by Co-administration with P-Glycoprotein Inhibitor Silymarin in Rats-
dc.typeMaster's Thesis-
dc.format.pagexi, 50 p.-
dc.identifier.major대학원 생명·약학부약학전공- 2-
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