새로운 CCR-2 길항제, YJC-10592의 약물동력학 연구
Pharmacokinetics of YJC-10592, a new chemokine receptor 2 (CCR-2) antagonist, in rat
- 주제(키워드) YJC-10592 , CCR-2 antagonist , HPLC , pharmacokinetics , dose-dependent
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2015
- 학위수여년월 2015. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학
- 실제URI http://www.dcollection.net/handler/ajou/000000019322
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
YJC-10592, a novel chemokine receptor 2 (CCR-2) antagonist, was synthesized for the therapy of atopic dermatitis and asthma. To evaluate the pharmacokinetic characteristics of YJC-10592, a high-performance liquid chromatographic (HPLC) method was developed for the determination of YJC-10592 in rat plasma, urine and tissue homogenates using YJC-10450 as an internal standard. The mobile phase was gradient of 50 mM acetate buffer (pH 3.0) in acetonitrile at a flow rate of 1.0 ml/min. Chromatograms were monitored at 230 nm ultraviolet (UV) detector. The retention times were 8.0 in YJC-10592 and 6.3 min in the internal standard, respectively. And the detection limits of YJC-10592 were 0.05 g/ml in rat plasma and 0.2 g/ml in urine, respectively. The within- and between-day coefficients of variation (CV) of the analysis were commonly low (less than 13.6 %) for rat plasma and urine samples. After intravenous administration of YJC-10592, 5, 10 and 20 mg/kg, to rats, the pharmacokinetics of YJC-10592 was dose-dependent from 20 mg/kg dose. The values of the area under the plasma concentration-time curve from the time zero to the time infinite (AUC), the time-averaged total body (CL) and nonrenal (CLNR) clearance of YJC-10592 were dose-dependent from 20 mg/kg. CL and CLNR of YJC-10592 were significantly low at dose of 20 mg/kg compared to those at 5 and 10 mg/kg, suggesting that saturable metabolism might be involved. After YJC-10592 was orally administration at doses of 100 and 200 mg/kg, to rats, the absolute bioavailability (F) values (4.01 and 1.89% for 100 and 200 mg/kg, respectively) was low, taking into absorption of the drug from rat gastrointestinal tract (90.2 and 88.4% absorbed for 100 and 200 mg/kg, respectively) and first-pass metabolism in the liver, stomach and/or metabolism might be one reason for this result. YJC-10592 had a good affinity to almost all rat tissues studied except brain and this was supported by a relatively high value of the apparent volume of distribution at steady state (Vss) (890-1385 ml/kg) after intravenous administration of YJC-10592 to rats.
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ABSTRACT ⅰ
TABLE OF CONTENTS ⅲ
LIST OF FIGURES ⅴ
LIST OF TABLES ⅶ
ABBREVIATIONS ⅷ
Ⅰ. INTRODUCTION 1
Ⅱ. MATERIALS AND METHODS 3
A. Chemicals 3
B. Animal 3
C. Preparation of standard solutions 3
D. Sample preparations 4
E. HPLC apparatus 4
F. Intravenous study 5
G. Oral study 6
H. Tissue distribution study 6
I. Pharmacokinetic analysis 7
J. Statistical analysis 8
Ⅲ. RESULTS 9
A. Validation of HPLC method 9
B. Intravenous study 18
C. Oral study 21
D. Tissues distribution study 24
Ⅳ. DISCUSSION 26
Ⅴ. CONCLUSION 28
REFERENCES 29
KOREAN ABSTRACT 32
