Effect of Hepatic Impairment on OATP1B Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs

药代动力学 生物标志物 体内 药理学 医学 人口 曲线下面积 药品 内科学 内生 队列 化学 生物 生物化学 环境卫生 生物技术
作者
Jian Lin,Emi Kimoto,Shinji Yamazaki,Manoli Vourvahis,Arthur Bergman,A. David Rodrigues,Chester Costales,Rui Li,Manthena V. S. Varma
出处
期刊:Clinical Pharmacology & Therapeutics [Wiley]
卷期号:113 (5): 1058-1069 被引量:22
标识
DOI:10.1002/cpt.2829
摘要

Hepatic impairment (HI) is known to modulate drug disposition and may lead to elevated plasma exposure. The aim of this study was to quantitate the in vivo OATP1B-mediated hepatic uptake activity in populations with varying degrees of HI. First, we measured baseline levels of plasma coproporphyrin-I, an endogenous OATP1B biomarker, in an open-label, parallel cohort study in adult subjects with normal liver function and mild, moderate, and severe HI (n = 24, 6/cohort). The geometric mean plasma concentrations of coproporphyrin-I were 1.66-fold, 2.81-fold (P < 0.05), and 7.78-fold (P < 0.0001) higher in mild, moderate, and severe impairment than those healthy controls. Second, we developed a dataset of 21 OATP1B substrate drugs with HI data extracted from literature. Median disease-to-healthy plasma area under the curve (AUC) ratios for substrate drugs were ~ 1.4, 3.0, and 6.4 for mild, moderate, and severe HI, respectively. Additionally, significant linear relationship was noted between AUC ratios of substrate drugs without and with co-administration of rifampin, a prototypic OATP1B inhibitor, and AUC ratios in moderate (P < 0.01) and severe (P < 0.001) HI. Third, a physiologically-based pharmacokinetic model analysis was conducted with 10 substrate drugs following estimation of relative OATP1B functional activity in virtual disease population models using coproporphyrin-I data and verification of substrate models with rifampin drug-drug interaction data. This approach adequately predicted plasma AUC change particularly in moderate (9 of 10 within 2-fold) and severe (5 of 5 within 2-fold) HI. Collective findings indicate progressive reduction, by as much as 90-92%, in OATP1B activity in the HI population.
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
嘿嘿应助LYB吕采纳,获得10
1秒前
2秒前
Qwe发布了新的文献求助10
3秒前
隐形曼青应助宋宋采纳,获得10
4秒前
田様应助45采纳,获得10
4秒前
蜂蜜罐zi完成签到,获得积分10
5秒前
搜集达人应助魏少爷采纳,获得10
5秒前
FashionBoy应助冬至季采纳,获得10
5秒前
Yuntao_Chen发布了新的文献求助10
5秒前
5秒前
鸭梨鸭梨发布了新的文献求助10
8秒前
8秒前
火星上书本完成签到,获得积分20
9秒前
科研通AI2S应助sciDoge采纳,获得10
10秒前
吴祥坤发布了新的文献求助10
10秒前
11秒前
量子星尘发布了新的文献求助10
13秒前
13秒前
13秒前
13秒前
14秒前
感谢大家完成签到,获得积分10
15秒前
WQ发布了新的文献求助10
16秒前
hai完成签到,获得积分10
17秒前
17秒前
眯眯眼的雪莲完成签到 ,获得积分10
18秒前
19秒前
天气好好发布了新的文献求助10
19秒前
19秒前
小六九完成签到 ,获得积分10
20秒前
21秒前
21秒前
22秒前
24秒前
冬至季发布了新的文献求助10
25秒前
英吉利25发布了新的文献求助10
26秒前
26秒前
WQ完成签到,获得积分10
26秒前
27秒前
28秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 700
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
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 3975814
求助须知:如何正确求助?哪些是违规求助? 3520123
关于积分的说明 11201020
捐赠科研通 3256502
什么是DOI,文献DOI怎么找? 1798347
邀请新用户注册赠送积分活动 877523
科研通“疑难数据库(出版商)”最低求助积分说明 806417