title: Development and application of a multiroute physiologically based pharmacokinetic model for oxytetracycline in dogs and humans.
abstract: Oxytetracycline (OTC) is a commonly used tetracycline antibiotic in veterinary and human medicine. To establish a quantitative model for predicting OTC plasma and tissue exposure, a permeability-limited multiroute physiologically based pharmacokinetic model was developed in dogs. The model was calibrated with plasma pharmacokinetic data in beagle dogs following single intravenous (5 mg/kg), oral (100 mg/kg), and intramuscular (20 mg/kg) administrations. The model predicted other available dog data well, including drug concentrations in the liver, kidney, and muscle after repeated exposure, and data in the mixed-breed dog. The model was extrapolated to humans and the human model adequately simulated measured plasma OTC concentrations after intravenous (7.14 mg/kg) and oral exposures (6.67 mg/kg). The dog model was applied to predict 24-h OTC area-under-the-curve after three therapeutic treatments. Results were 27.75, 51.76, and 64.17 μg/mL*h in the plasma, and 120.93, 225.64, and 279.67 μg/mL*h in the kidney for oral (100 mg/kg), intravenous (10 mg/kg), and intramuscular (20 mg/kg) administrations, respectively. This model can be used to predict plasma and tissue concentrations to aid in designing optimal therapeutic regimens with OTC in veterinary, and potentially, human medicine; and as a foundation for scaling to other tetracycline antibiotics and to other animal species. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:233-243, 2015.
authors.affiliation: Institute of Computational Comparative Medicine (ICCM) and The Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, 66506.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.forename: Mengjie
authors.initials: M
authors.lastname: Li
authors.forename: Ronette
authors.initials: R
authors.lastname: Gehring
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017849:Animals, Inbred Strains; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D019295:Computational Biology; D003198:Computer Simulation; D062313:Databases, Pharmaceutical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008954:Models, Biological; D010118:Oxytetracycline / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010601:Pharmacology, Clinical / Q000379:methods*; D010828:Physiology, Comparative / Q000379:methods*; D065667:Renal Elimination; D015203:Reproducibility of Results; D013045:Species Specificity; D014018:Tissue Distribution; D014730:Veterinary Medicine / Q000379:methods*
chemical_list: D000900:Anti-Bacterial Agents; D010118:Oxytetracycline
keywords: Food Animal Residue Avoidance Databank (FARAD); computational ADME; disposition; dogs; in silico modeling; mathematical model; oxytetracycline; pharmacokinetics; physiologically based pharmacokinetic (PBPK) modeling; tetracycline antibiotics