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Using pharmacokinetic modeling to determine the effect of drug and food on gastrointestinal transit in dogs
Department of Safety Pharmacology, Safety Assessment Sweden, AstraZeneca, Research and Development, Innovative Medicines, SE-151 85 Södertälje, Sweden. (Gastroenterology & Hepatology)
2011 (English)In: Journal of pharmacological and toxicological methods, ISSN 1056-8719, E-ISSN 1873-488X, Vol. 64, no 1, 42-52 p.Article in journal (Refereed) Published
Abstract [en]

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 15 min intravenous infusion of vehicle, atropine (0.06 mg/kg) or erythromycin (1 mg/kg) followed by an intragastric administration of a mixture of paracetamol (24 mg/kg) and sulfasalazine (20 mg/kg). Food was given just before or at 6 h 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.

Discussion: 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 andSITT 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.

Place, publisher, year, edition, pages
Elsevier, 2011. Vol. 64, no 1, 42-52 p.
Keyword [en]
Gastric emptying, Paracetamol, Pharmacokinetics, Small intestinal transit time, Sulfapyridine
National Category
Medical and Health Sciences
Research subject
Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-222663DOI: 10.1016/j.vascn.2011.04.008OAI: oai:DiVA.org:uu-222663DiVA: diva2:712004
Available from: 2014-04-12 Created: 2014-04-12 Last updated: 2017-12-05Bibliographically approved

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Al-Saffar, Ahmad

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