Document Detail

Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond.
MedLine Citation:
PMID:  23331046     Owner:  NLM     Status:  MEDLINE    
INTRODUCTION: Membrane transporters have been recognized to play a key role in determining the absorption, distribution and elimination processes of drugs. The organic anion-transporting polypeptide (OATP)1B1 and OATP1B3 isoforms are selectively expressed in the human liver and are known to cause significant drug-drug interactions (DDIs), as observed with an increasing number of drugs. It is evident that DDIs involving hepatic transporters are capable of altering systemic, as well as tissue-specific, exposure of drug substrates resulting in marked differences in drug safety and/or efficacy. It is therefore essential to quantitatively predict such interactions early in the drug development to mitigate clinical risks.
AREAS COVERED: The role of hepatic uptake transporters in drug disposition and clinical DDIs has been reviewed with an emphasis on the current state of the models applicable for quantitative predictions. The readers will also gain insight into the in vitro experimental tools available to characterize transport kinetics, while appreciating the knowledge gaps in the in vitro-in vivo extrapolation (IVIVE), which warrant further investigation.
EXPERT OPINION: Static and dynamic models can be convincingly applied to quantitatively predict drug interactions, early in drug discovery, to mitigate clinical risks as well as to avoid unnecessary clinical studies. Compared to basic models, which focus on individual processes, mechanistic models provide the ability to assess DDI potential for compounds with systemic disposition determined by both transporters and metabolic enzymes. However, complexities in the experimental tools and an apparent disconnect in the IVIVE of transport kinetics have limited the physiologically based pharmacokinetic modeling strategies. Emerging data on the expression of transporter proteins and tissue drug concentrations are expected to help bridge these gaps. In addition, detailed characterization of substrate kinetics can facilitate building comprehensive mechanistic models.
Hugh A Barton; Yurong Lai; Theunis C Goosen; Hannah M Jones; Ayman F El-Kattan; James R Gosset; Jian Lin; Manthena V Varma
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2013-01-21
Journal Detail:
Title:  Expert opinion on drug metabolism & toxicology     Volume:  9     ISSN:  1744-7607     ISO Abbreviation:  Expert Opin Drug Metab Toxicol     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-09-25     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  101228422     Medline TA:  Expert Opin Drug Metab Toxicol     Country:  England    
Other Details:
Languages:  eng     Pagination:  459-72     Citation Subset:  IM    
Pfizer Worldwide Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Eastern Point Road, Groton, CT 06340, USA.
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MeSH Terms
Cell Line
Drug Evaluation, Preclinical
Drug Interactions
Fluorobenzenes / pharmacokinetics,  therapeutic use
Hepatocytes / drug effects,  metabolism
Liver / cytology*,  drug effects*,  metabolism
Membrane Transport Proteins / drug effects*
Models, Theoretical
Physicochemical Phenomena
Pravastatin / pharmacokinetics,  therapeutic use
Pyrimidines / pharmacokinetics,  therapeutic use
Sulfonamides / pharmacokinetics,  therapeutic use
Reg. No./Substance:
0/Fluorobenzenes; 0/Membrane Transport Proteins; 0/Pyrimidines; 0/Sulfonamides; 287714-41-4/rosuvastatin; 81093-37-0/Pravastatin

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