Abstract：
:Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification-based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry-based quantitative proteomics as a sensitive, robust, and high-throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Sharma S,Suresh Ahire D,Prasad Bdoi
10.1002/jcph.1709subject
Has Abstractpub_date
2020-10-01 00:00:00pages
S17-S35eissn
0091-2700issn
1552-4604journal_volume
60 Suppl 1pub_type
杂志文章abstract：:In a double-blind, randomized, crossover study in ten patients with asthma, the effects on specific airway resistance of esmolol, a new ultra-short-acting beta 1-selective adrenoceptor blocker, were compared with those of placebo. Specific airway resistance was measured during increasing doses of esmolol infusion, dur...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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pub_type： 杂志文章
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journal_title：Journal of clinical pharmacology
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doi：10.1177/009127009203200608
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journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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pub_type： 杂志文章
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pub_type： 杂志文章
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更新日期：1989-11-01 00:00:00
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章
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更新日期：2002-07-01 00:00:00
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journal_title：Journal of clinical pharmacology
pub_type： 历史文章,杂志文章
doi：10.1177/00912700022009710
更新日期：2000-09-01 00:00:00
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pub_type： 杂志文章,多中心研究
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更新日期：2015-02-01 00:00:00
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journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
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更新日期：1975-05-01 00:00:00
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章,随机对照试验
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更新日期：2007-09-01 00:00:00
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journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
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journal_title：Journal of clinical pharmacology
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journal_title：Journal of clinical pharmacology
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更新日期：1988-08-01 00:00:00
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pub_type： 杂志文章,评审
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更新日期：1993-08-01 00:00:00
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