View : 931 Download: 0

Full metadata record

DC Field Value Language
dc.contributor.advisor이병구-
dc.contributor.author이은지-
dc.creator이은지-
dc.date.accessioned2016-08-26T04:08:19Z-
dc.date.available2016-08-26T04:08:19Z-
dc.date.issued2014-
dc.identifier.otherOAK-000000083701-
dc.identifier.urihttps://dspace.ewha.ac.kr/handle/2015.oak/211019-
dc.identifier.urihttp://dcollection.ewha.ac.kr/jsp/common/DcLoOrgPer.jsp?sItemId=000000083701-
dc.description.abstractMetoprolol은 선택적인 adrenergic β1 receptor 차단제로서 주로 간의 cytochrome P450s (CYPs)에 의해서 대사된다. 본 박사학위 논문에서는 당뇨 rat 모델인 DMIS rat과 그 대조군 rat에 정맥 및 경구로 1.5 mg/kg 용량의 metoprolol을 투여했을 때 두 그룹간 pharmacokinetics 변화를 비교하였다. Metoprolol은 intermediate HER (간 추출율)을 가지는 약물로서 간 대사 정도는 간 혈류속도(QH), 혈장 단백 비결합 약물 분율 (fp), in vitro 실험으로 구한 hepatic CLint값에 의존한다. 본 실험결과 DMIS rat과 그 대조군 rat 사이에 in vitro hepatic CLint와 fp값이 유의적인 차이를 나타내지 않았다. Metoprolol을 DMIS rat과 그 대조군 rat에 정맥으로 투여한 결과, DMIS rat의 CLNR이 40.2% 빨라졌으며 (DMIS; 157 ml/min/kg, 대조군; 112 ml/min/kg), DMIS rat의 AUC가 27.9% 감소하였다 (DMIS; 8.72μg min/ml, 대조군; 12.1 μg min/ml). 또한 metoprolol을 DMIS rat과 그 대조군 rat에 경구로 투여한 결과, 두 그룹 모두 위장관에서 투여한 용량의 99% 이상이 흡수되었음에도 DMIS rat의 AUC가 30.0% 감소하였다 (DMIS; 1.98 μg min/ml, 대조군; 2.83 μg min/ml). DMIS rat에서 정맥, 경구 투여 시 모두 AUC가 감소하는 결과를 보인 것은 대조군에 비해 DMIS rat의 간 혈류 속도(QH)가 빨라짐으로 인해 CLH (CLNR)이 빨라진 결과로 판단된다. Rat을 대상으로 한 이번 실험결과를 사람을 대상으로 조심스럽게 응용해보면, 당뇨 환자의 metoprolol 간 대사 속도가 빨라져 임상적으로 pharmacokinetics 변화를 초래할 수 있는 잠재적 가능성이 있다고 볼 수 있다. 하지만 1형 당뇨 환자를 대상으로 cytochrome P450s (CYPs)의 변화에 대하여 연구한 결과가 부족하고, 당뇨 환자에게 약물의 pharmacokinetics-pharmacodynamics를 변화시키는 다양한 요인들이 존재하므로 이 가설을 증명하기 위해서는 사람을 대상으로 한 연구가 필요하다.;Metoprolol is a selective β1-adrenergic receptor antagonist metabolized by hepatic cytochrome P450s (CYPs). In this study, we evaluated pharmacokinetic changes following intravenous (i.v.) and oral metoprolol in rats with diabetes mellitus induced by streptozotocin (DMIS). Metoprolol has an intermediate hepatic extraction ratio in rats (0.586–0.617), and it is assumed that the liver is exclusively responsible for metoprolol metabolism. Thus, the hepatic clearance, CLH (the non-renal clearance, CLNR) of metoprolol depends on the hepatic blood flow rate (QH), the free fraction in plasma (fp), and in vitro hepatic intrinsic clearance, CLint. After i.v. administration of 1.5 mg/kg metoprolol to DMIS rats, its CLNR was 40.2% faster than control animals. This could be due to a significantly faster QH because hepatic CLint and fp were comparable between the two groups of rats due to unchanged hepatic CYP2D activity. After oral administration of 1.5 mg/kg metoprolol to DMIS rats, gastrointestinal absorption was > 99% of the oral dose for both groups, while the area under the plasma concentration–time curve (AUC) was 30.0% smaller, which could be caused by the greater hepatic metabolism seen in the i.v. study. In terms of extrapolating these data to humans carefully, we conclude that accelerated hepatic clearance of metoprolol has the potential to cause clinically relevant pharmacokinetic changes in patients with diabetes. Human studies should be performed to validate this hypothesis.-
dc.description.tableofcontentsⅠ. INTRODUCTION 1 Ⅱ. MATERIALS AND METHODS 6 A. Materials 6 B. Animals 6 C. Induction of Diabetes Mellitus in Rats by Streptozotocin Injection 7 D. Preliminary Study 7 E. In Vitro Study 8 1. Preparation of Hepatic and Intestinal Microsomes 8 2. Measurement of Metoprolol Vmax, Km, and CLint in Hepatic and Intestinal Microsomes 10 3. Measurement of Rat Plasma Protein Binding of Metoprolol Using Equilibrium Dialysis 11 F. In Vivo Study 12 1. Pretreatment of Rats for the Intravenous and Oral Studies 12 2. Intravenous study 13 3. Oral Study 14 G. HPLC Analysis of Metoprolol 15 1. Instrument and Chromatographic Conditions 15 2. Preparation of Calibration Standards and Quality Control Samples 15 3. Sample Preparation 16 4. Method Validation 16 a. Selectivity and Linearity 16 b. Accuracy and Precision 17 c. Recovery 17 H. Pharmacokinetic Analysis 18 I. Statistical Analysis 19 Ⅲ. RESULTS 20 A. Preliminary Study 20 B. In Vitro studies 23 1. Vmax, Km, and CLint for Metoprolol in Hepatic and Intestinal Microsomes 23 C. In Vivo Studies 32 1. Pharmacokinetics of Metoprolol after Single Intravenous Administration of Metoprolol 32 2. Pharmacokinetics of Metoprolol after a Single Oral Administration of Metoprolol 32 D. HPLC Analysis 40 Ⅳ. DISCUSSION 43 Ⅴ. CONCLUSION 49 REFERENCES 50 ABSTRACT IN KOREAN 59-
dc.formatapplication/pdf-
dc.format.extent3656755 bytes-
dc.languageeng-
dc.publisher이화여자대학교 대학원-
dc.subject.ddc600-
dc.titleFaster non-renal clearance of metoprolol in streptozotocin-induced diabetes mellitus rats-
dc.typeDoctoral Thesis-
dc.format.pagevii, 60 p.-
dc.identifier.thesisdegreeDoctor-
dc.identifier.major대학원 생명·약학부약학전공-
dc.date.awarded2014. 2-
Appears in Collections:
일반대학원 > 생명·약학부 > Theses_Ph.D
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

BROWSE