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Rat에서의 Ranitidine제제의 생체내이용율

Rat에서의 Ranitidine제제의 생체내이용율
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대학원 약학과
이화여자대학교 대학원
Rat에서의 ranitidine(RT)제제의 bioavai1ability(BA)를 검토하고자 먼저 RT제제의 체내동태를 살펴보고, 국내에서 시판되고 있는 A, B, C 세 제약회사의 RT제제의 pharrnacokinetic parameter를 비교검토하였다. 또한 사람에서의 혈중약물농도를 rat으로부터 얻은 pharmacokinetic parameter로부터 예측할 수 있는지를 검토하였다. Rat에 RT·HCl을 10mg/kg으로 정맥주사하였고, RT·HCl solution 또는 RT제제의 crushed sample을 RT·HCl 50mg/kg으로 경구투여하였다. RT혈중약물농도는 HPLC로 정량하였다. 혈중으로부터의 RT은 biexponential 양상으로 빠르게 감소하였다. Crushed sample A, B, C 및 RT solution을 각각 rat에게 경구투여시 사람에서처럼 double peak가 나타났고, Pharmacokinetic parameter를 비교하였을 때 T_(max2)만 유의적 차이를 보였다(p<0.05). Crushed sample A, B 및 C의 AUC, C_(max) 및 T_(max)를 비교하였을 때 AUC, C_(max2) 및 T_(max1)에서 crushed sample A, B 및 C간에 유의적 차이가 없었고 각각의 BA는 54.6, 40.7 및 40.0%였다. 그러나 C_(max1)에서 crushed sample A, B간에 유의적 차이가 나타났고(p<0.05), T_(max2)에서 crushed sample A, C간에 유의적 차이를 보였다(p<0.05). 그러나 RT제제의 치료 특징상 약효의 빠른 발현시간을 요구하지 않고, 하루에 2번씩 장시간 치료하므로 C_(max1), T_(max2)의 유의적인 차는 약효발현에 영향을 미친다고는 할 수 없다. 본 rat흡수실험에서 얻은 RT pharmacokinetic data와 문헌에서 얻은 dog 및 사람에서의 RT pharrnacokinetic data를 비교분석할 때 RT의 체내동태는 종차간에 유사성이 있었고, Cll_(t)와 Vd_(sa)에서 유의적인 종차간의 상관관계가 있었다. 따라서 rat의 RT pharmacokinetic data로부터 사람의 pharmacokinetic data를 예측가능하다고 사료된다.;Comparison of bioavailability(BA) of three brands of ranitidine(RT) tablet has been studied in rats. The purpose of this study was to characterize the pharmacokinetics of RT tablets in the rat and to compare pharmacokinetic parameters of three brands of RT tablet. In addition, It was investigated whether plasma RT concentrations in humans can be predicted from pharmacokinetic parameters obtained in rats. RT was administered intravenously in dose of RT·HCl 10mg/kg and orally in dose of RT·HCl 50mg/kg as solution or crushed sample. Plasma RT concentrations were determined by HPLC. Plasma RT concentrations as a function of time were fitted to two compartment model. Plasma RT concentrations declined with a terminal half life(t_(1/2β))of 40.9min. The plasma concentration-time curve showed two peak plasma concentrations following an oral administration of solution or crushed sample in rats like humans. No significant difference among pharmacokinetic parameters was observed except T_(max2)(P<0.05). In compared with BA of three crushed samples, C_(max1) was showed significant difference between crushed sample A and B(p<0.05), and T_(max2) was showed significant difference between crushed sample A and C(p<0.05). The BA for crushed sample A, B and C were found to be 54.6, 40.7 and 40.0%, respectively, Equivalence of C_(max1) and T_(max2) were guaranteed in this study, However, it was concluded that three brands of RT tablet are bioequivalent, taking the following characteristics of RT into consideration; (1) rapid onset of the effect is not required, (2) C_(max1) and T_(max2) do not seem to influence the effectiveness of the drug during a long-term treatment by the usual administration of twice a day. Results from this study were combined with pharmacokinetic data for RT in dogs and humans to develop a basis for interspecies scale-up of the disposition characteristics of the drug. There were similarities in the general disposition of the drug. Allometric relationships were sought between pharmacokinetic parameters and species body weight. Significant interspecies correlations were found for total body clearance(Cl_(t))and steady state volume of distribution(Vd_(ss)). Thus, plasma RT concentrations in humans can be predicted from pharmacokinetic parameters obtained in rats.
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