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새로운 CCR-2 길항제, YJC-10592의 약물동력학 연구
- Author(s)
- 두은신
- Advisor
- 김소희
- Department
- 일반대학원 약학
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2015-02
- Language
- eng
- Keyword
- YJC-10592; CCR-2 antagonist; HPLC; pharmacokinetics; dose-dependent
- Alternative Abstract
- 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.
- Fulltext
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- Graduate School of Ajou University > Department of Pharmacy > 3. Theses(Master)
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