Document Detail

Using pharmacokinetic modeling to determine the effect of drug and food on gastrointestinal transit in dogs.
MedLine Citation:
PMID:  21596146     Owner:  NLM     Status:  Publisher    
INTRODUCTION: The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively. METHODS: In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15min intravenous infusion of vehicle, atropine (0.06mg/kg) or erythromycin (1mg/kg) followed by an intragastric administration of a mixture of paracetamol (24mg/kg) and sulfasalazine (20mg/kg). Food was given just before or at 6h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT. RESULTS: The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT. CONCLUSION: Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development.
Linnea Sjödin; Sandra Visser; Ahmad Al-Saffar
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-8
Journal Detail:
Title:  Journal of pharmacological and toxicological methods     Volume:  -     ISSN:  1873-488X     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9206091     Medline TA:  J Pharmacol Toxicol Methods     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Inc.
Department of Safety Pharmacology, Safety Assessment Sweden, AstraZeneca, Research and Development, Innovative Medicines, SE-151 85 Södertälje, Sweden.
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