title: Pharmacokinetics of paracetamol in Göttingen minipigs: in vivo studies and modeling to elucidate physiological determinants of absorption.
abstract: OBJECTIVE
  Onset and rate of gastric emptying are important determinants of drug absorption after oral dosing. Therefore, robust estimates of these parameters are needed in physiologically based absorption models to predict reliably plasma concentration time profiles. For human and some other laboratory animals, reasonable parameterization of gastric emptying has been established. However gastric emptying is less well characterized in minipigs, a large animal model rapidly gaining importance in pharmaceutical research.
  
  
  METHODS
  A pharmacokinetic crossover study using different dosage forms of paracetamol (intravenous and oral solution, capsule and tablet) was conducted in four male and four female Göttingen minipigs after an overnight fast. Deconvolution analysis was performed to determine the absorption kinetics. Estimated lag times and first order gastric emptying parameters were incorporated in a previously published PBPK model of the minipig and simulations verified. Postmortem assessments of minipig stomachs were made after different fasting protocols.
  
  
  RESULTS
  Fraction of dose absorbed vs. time profiles showed high interindividual variability, comparable to human fed state absorption. Mean gastric transit times were determined to be 0.63 h, 1.36 h, and 0.73 h for solution, capsules, and tablets, respectively. Postmortem assessment confirmed that minipig stomachs were not empty after an overnight fast.
  
  
  CONCLUSIONS
  Gastric transit times in overnight fasted minipigs are longer than those observed in humans. This is most likely caused by delayed and incomplete food emptying and further work is needed to develop feasible and effective fasting protocols for minipigs.
authors.affiliation: Pharmaceutical Sciences, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland, claudiasuenderhauf@hotmail.com.
authors.forename: Claudia
authors.initials: C
authors.lastname: Suenderhauf
authors.forename: Gerald
authors.initials: G
authors.lastname: Tuffin
authors.forename: Helle
authors.initials: H
authors.lastname: Lorentsen
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Grimm
authors.forename: Christophe
authors.initials: C
authors.lastname: Flament
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
mesh_terms: D065567:Absorption, Physiological / Q000502:physiology*; D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D005215:Fasting; D005260:Female; D005746:Gastric Emptying / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism*; D005766:Gastrointestinal Contents; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D013552:Swine; D013556:Swine, Miniature
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen