CHOSUN

Pharmacokinetic interaction between Losartan and Ticlopidine in rats.

Metadata Downloads
Author(s)
김형기
Issued Date
2009
Abstract
The present study was to investigate the effect of ticlopidine, antiplatelet drug, on the pharmacokinetics of losartan, which is substrates of CYP3A4, 2C9 and P-gp, and its active metabolite, EXP-3174, in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after an oral administration of losartan (9 mg/kg) in the presence or absence of ticlopidine (4 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of ticlopidine compared with the control group (given losartan alone). Presence of ticlopidine significantly (p<0.05 4mg/kg; p < 0.01, 10 mg/kg) increased the area under the plasma concentration?time curve (AUC) of losartan by 30.7?73.1% and peak plasma concentration (Cmax) of losartan by 17.3?40.0% increased, total plasma clearance (CL/F) of losartan by 23.5?42.3% decreased. However there were no significant changes in the volume of distribution(Vdss), Tmax and terminal half life(t1/2) of losartan in the presence of ticlopidine. Consequently, the absolute bioavailability (AB) of losartan in the presence of ticlopidine was 20.6?27.3%, which was enhanced significantly (<0.05 4mg/kg; p < 0.01, 10 mg/kg) compared with the oral control group (15.8%). The relative bioavailability (RB) of losartan increased by 1.30 to 1.72 fold in the presence of ticlopidine. Presence of ticlopidine (10 mg/kg) significantly increased the AUC (41.4%) of EXP-3174 compared with the control group. The metabolite-parent AUC ratio (MR) was significantly (P<0.05) decreased by 10.1-18.2% in the presence of ticlopidine (4 and 10mg/kg) compared to that in the control group. However there were no significant changes in the volume of distribution(Vdss), Tmax and terminal half life(t1/2) of EXP-3174 in the presence of ticlopidine. Ticlopidine significantly enhanced bioavailabiliy of losartan in rats. The increased bioavailability was due to inhibition of the CYP3A4 and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and furthermore, due to decreased total body clearance(CL/F) of losartan. However, there was no involvement of P-gp in our in vitro study. In conclusion, the presence of ticlopidine significantly enhanced the bioavailability of losartan. So, concurrent use of ticlopidine with losartan should require close monitoring for potential drug interactions in clinics.
Key words: Losartan, EXP-3174, Ticlopidine, Pharmacokinetics, CYP, P-gp, Rat.|로살탄(losartan)은 CYP3A4, CYP2C9, P-gp의 기질이며 순환기계 약물로서 안지오텐신 수용체를 차단하여 고혈압치료에 널리 사용된다. 티크로피딘(ticlopidine)은 항혈소판작용을 하여 주로 심장질환 특히 관상동맥 질환인 협심증 예방 및 치료 처방으로 빈용되고 있다. 따라서 본 실험에서는 흰쥐에게 티크로피딘 (4mg/kg 및 10 mg/kg)과 로살탄을 경구 (9 mg/kg) 병용투여하였을 때 로살탄 및 그 활성대사체인 EXP-3174의 약물동태학적 파라미터를 연구검토하였다.
티크로피딘과 동시투여하였을 때 로살탄의 약물동태학적 파라미터는 유의성 있게 변화 하였다. 혈장농도곡선하면적 (AUC)는 티크로피딘 병용투여군에서 대조군에 비해 유의성 (4mg/kg, P<0.05; 10mg/kg, P<0.01)있게 증가하였으며 최고혈중농도 (Cmax)도 유의성 (p<0.05) 있게 증가하였다. 토탈클리어런스(CL/F)는 유의성(4mg/kg, P<0.05; 10mg/kg, P<0.05)있게 감소하였다. 절대적생체이용율(AB)은 대조군에 비해 유의성 (4mg/kg, P<0.05; 10mg/kg, P<0.01) 있게 증가되었다. 그 결과로 상대적생체이용율(RB)이 1.30-1.72 배 증가되었다. 티크로피딘 병용투여군에서 소실반감기 (t1/2)는 유의성(10mg/kg, P<0.05) 있게 증가하였고, 분포용적(Vdss)은 대조군에 비해 감소하였으나 유의성은 없었다. 티크로피딘 병용투여군에서 최고혈중농도 도달시간은 유의성이 없었다.
로살탄의 활성대사체인 EXP-3174에서 혈장농도곡선하면적 (AUC)는 티크로피딘 병용투여군에서 유의성 (10mg/kg, P<0.05) 있게 증가하였으며 토탈클리어런스(CL/F)는 유의성(10mg/kg, P<0.05) 있게 감소하였다. 최고혈중농도 (Cmax)도 유의성 (p<0.05) 있게 증가하였다. 분포용적(Vdss)은 대조군에 비해 감소하였으나 유의성이 없었고 소실반감기(t1/2)는 대조군에 비해 증가하였으나 유의성이 없었다. 또한 P-gp기질인 로살탄에 대해서 티크로피딘의 P-gp에 대한 영향은 거의 없었다.
본 연구에서 고혈압 치료제인 로살탄과 항혈소판제인 티크로피딘을 동시투여하였을 때 경구투여 시킨 로살탄의 생체이용률의 증가는 CYP3A4, 2C9의 억제와 토탈클리어런스의 감소로 인한 것으로 사료된다. 본 연구결과를 토대로, 임상에서 티크로피딘과 로살탄의 병용투여시 로살탄의 용량을 조절하는 것이 바람직하다고 사료된다.
Alternative Title
흰 쥐에서 로살탄과 티클로피딘의 상호작용
Alternative Author(s)
Kim, Hyung
Affiliation
조선대학교 약학대학 약제학 교실
Department
일반대학원 약학과
Advisor
최준식
Awarded Date
2010-02
Table Of Contents
CONTENTS

Abstract 1
국문초록 3
1. Introduction 5
2. Materials and Methods 7
2.1. Chemicals 7
2.2. Drug administration 7
2.3. Method and assay 8
2.3.1. HPLC assay 8
2.3.2. CYP inhibition assay 9
2.3.3. Rhodamine-123 retention assay 9
2.4. Pharmacokinetic analysis? 10
2.5. Statistical analysis? 10
3. Results and Discussion 11
4. Conclusion 13
References 14
Degree
Master
Publisher
조선대학교
Citation
김형기. (2009). Pharmacokinetic interaction between Losartan and Ticlopidine in rats.
Type
Dissertation
URI
https://oak.chosun.ac.kr/handle/2020.oak/8406
http://chosun.dcollection.net/common/orgView/200000239182
Appears in Collections:
General Graduate School > 3. Theses(Master)
Authorize & License
  • AuthorizeOpen
  • Embargo2010-01-25
Files in This Item:

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.