Nonlinear Pharmacokinetics

药代动力学 生物利用度 化学 游离分数 药理学 药品 吸收(声学) 医学 稳态(化学) 普萘洛尔 内分泌学 材料科学 物理化学 复合材料
作者
Thomas M. Ludden
出处
期刊:Clinical Pharmacokinectics [Adis, Springer Healthcare]
卷期号:20 (6): 429-446 被引量:183
标识
DOI:10.2165/00003088-199120060-00001
摘要

Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. One of the more important sources of nonlinearity is the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine. In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the overall systemic availability. The binding of drugs to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. This can cause pharmacokinetic parameters based on total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters based on free drug concentration appear linear. An important consideration in regard to concentration-dependent serum binding is the difficulty in relating total concentration to a usual therapeutic range if free concentration is a better indicator of drug effect. Measurement of free concentration is needed in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is valproic acid. Partial saturation of elimination pathways can result in the well known behaviour typical of Michaelis-Menten pharmacokinetics. Small changes in dosing rate can make much larger differences in steady-state concentration. The time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate. Alcohol and phenytoin are examples of drugs that exhibit such behaviour. The sensitivity of steady-state concentration and cumulation rate to changes in dosing rate are both influenced by the magnitude of parallel first-order elimination pathways: even a first-order pathway that is only 1 to 2% of maximum clearance (which occurs at very low concentration) can be an important determinant of steady-state concentration and cumulation rate when concentrations are high. Theophylline and salicylate have significant parallel first-order elimination pathways as well as saturable pathways. Autoinduction causes an increase in clearance with long term administration. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose- or concentration-dependent must be kept in mind. Carbamazepine is a major example of autoinduction. It is fortunate that only a few of the many hundreds of drugs in use exhibit nonlinear behaviour that leads to clinical implications.(ABSTRACT TRUNCATED AT 400 WORDS)
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
尉迟剑心发布了新的文献求助10
刚刚
2秒前
优雅的千凝完成签到,获得积分10
2秒前
fox2shj完成签到,获得积分10
3秒前
sai完成签到,获得积分10
3秒前
6秒前
老迟到的土豆完成签到 ,获得积分10
6秒前
cuber完成签到 ,获得积分10
8秒前
12发布了新的文献求助10
8秒前
8秒前
9秒前
ylj发布了新的文献求助10
10秒前
www完成签到 ,获得积分10
12秒前
星海梦幻完成签到 ,获得积分10
12秒前
13秒前
abcd发布了新的文献求助10
13秒前
量子星尘发布了新的文献求助10
14秒前
16秒前
17秒前
Hello应助Expelliarmus采纳,获得10
18秒前
15357058526完成签到 ,获得积分10
18秒前
19秒前
聪明白羊完成签到,获得积分10
19秒前
20秒前
smottom应助weixiaozdw采纳,获得10
21秒前
成就井发布了新的文献求助10
23秒前
思思完成签到 ,获得积分10
24秒前
26秒前
26秒前
zzy完成签到 ,获得积分10
30秒前
慕青应助foreverbigbao采纳,获得30
32秒前
32秒前
33秒前
理想国的过客完成签到,获得积分10
33秒前
34秒前
学姐完成签到,获得积分10
35秒前
35秒前
15357058526关注了科研通微信公众号
37秒前
zhouzhou发布了新的文献求助20
37秒前
37秒前
高分求助中
Picture Books with Same-sex Parented Families: Unintentional Censorship 1000
A new approach to the extrapolation of accelerated life test data 1000
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 3977847
求助须知:如何正确求助?哪些是违规求助? 3521994
关于积分的说明 11211109
捐赠科研通 3259220
什么是DOI,文献DOI怎么找? 1799563
邀请新用户注册赠送积分活动 878417
科研通“疑难数据库(出版商)”最低求助积分说明 806888