Using pharmacokinetic modeling to determine the effect of drug and food on gastrointestinal transit in dogs

Abstract

IntroductionThe 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. MethodsIn 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. ResultsThe 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. DiscussionPopulation 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.