Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling

蛋白质组学 有机阴离子转运多肽 基于生理学的药代动力学模型 细胞色素P450 Abcg2型 定量蛋白质组学 药代动力学 药物代谢 药理学 运输机 生物化学 化学 药品 生物 ATP结合盒运输机 基因
作者
S.C. Sharma,Dilip Kumar Singh,Vijay Mettu,Guihua Yue,Deepak Ahire,Abdul Basit,Scott Heyward,Bhagwat Prasad
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (3): 1737-1749 被引量:10
标识
DOI:10.1021/acs.molpharmaceut.2c00950
摘要

Rats are extensively used as a preclinical model for assessing drug pharmacokinetics (PK) and tissue distribution; however, successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically relevant drug-metabolizing enzymes and transporters (DMETs) in the liver and different intestinal segments of Sprague-Dawley rats. The levels of DMET proteins in rats were quantified using the global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of the major DMET proteins was largely comparable using quantitative global and targeted proteomics. However, global proteomics-based TPA was able to detect and quantify a comprehensive list of 66 DMET proteins in the liver and 37 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502 and 74 to 2558 pmol/g tissue. P-gp abundance was higher in the intestine (124.1 pmol/g) as compared to that in the liver (26.6 pmol/g) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptides (Oatp) 1a1, 1a4, 1b2, and 2a1 and multidrug resistance proteins (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate the utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
刚刚
刚刚
1秒前
2秒前
量子星尘发布了新的文献求助10
2秒前
李李完成签到 ,获得积分10
3秒前
蒲公英发布了新的文献求助20
4秒前
4秒前
LUCCAS发布了新的文献求助20
5秒前
5秒前
三叔完成签到,获得积分0
5秒前
5秒前
Alicia发布了新的文献求助10
6秒前
ossantu发布了新的文献求助10
6秒前
finkle完成签到,获得积分10
7秒前
ZJH发布了新的文献求助10
7秒前
youxiu1112发布了新的文献求助10
7秒前
wwxd完成签到,获得积分10
8秒前
Ryan完成签到,获得积分20
8秒前
Jayce完成签到,获得积分10
9秒前
10秒前
10秒前
10秒前
10秒前
Kuseite完成签到,获得积分10
10秒前
迅速冰岚发布了新的文献求助10
10秒前
LPeaQ应助期待采纳,获得10
10秒前
nan完成签到,获得积分20
11秒前
魔幻代梅发布了新的文献求助10
12秒前
元气饱满完成签到,获得积分10
12秒前
13秒前
FunGuy发布了新的文献求助10
14秒前
简单谷梦发布了新的文献求助10
14秒前
orange完成签到,获得积分10
15秒前
晴天发布了新的文献求助10
15秒前
说书人完成签到,获得积分10
15秒前
15秒前
挖掘机应助鲤鱼凌波采纳,获得200
15秒前
ei123发布了新的文献求助30
15秒前
高分求助中
The Mother of All Tableaux Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 2400
Ophthalmic Equipment Market by Devices(surgical: vitreorentinal,IOLs,OVDs,contact lens,RGP lens,backflush,diagnostic&monitoring:OCT,actorefractor,keratometer,tonometer,ophthalmoscpe,OVD), End User,Buying Criteria-Global Forecast to2029 2000
Optimal Transport: A Comprehensive Introduction to Modeling, Analysis, Simulation, Applications 800
Official Methods of Analysis of AOAC INTERNATIONAL 600
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 588
T/CIET 1202-2025 可吸收再生氧化纤维素止血材料 500
Interpretation of Mass Spectra, Fourth Edition 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3951758
求助须知:如何正确求助?哪些是违规求助? 3497124
关于积分的说明 11086059
捐赠科研通 3227597
什么是DOI,文献DOI怎么找? 1784497
邀请新用户注册赠送积分活动 868586
科研通“疑难数据库(出版商)”最低求助积分说明 801154