title: A physiologically based pharmacokinetic model linking plasma protein binding interactions with drug disposition.
abstract: Combination drug therapy increases the chance for an adverse drug reactions due to drug-drug interactions. Altered disposition for sulfamethazine (SMZ) when concurrently administered with flunixin meglumine (FLU) in swine could lead to increased tissue residues. There is a need for a pharmacokinetic modeling technique that can predict the consequences of possible drug interactions. A physiologically based pharmacokinetic model was developed that links plasma protein binding interactions to drug disposition for SMZ and FLU in swine. The model predicted a sustained decrease in total drug and a temporary increase in free drug concentration. An in vivo study confirmed the presence of a drug interaction. Neither the model nor the in vivo study revealed clinically significant changes that alter tissue disposition. This novel linkage approach has use in the prediction of the clinical impact of plasma protein binding interactions. Ultimately it could be used in the design of dosing regimens and in the protection of the food supply through prediction and minimization of tissue residues.
authors: Food Animal Residue Avoidance Databank, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough St. Raleigh, NC 27606, USA. jbuur@westernu.edu
authors: J L
authors: JL
authors: Buur
authors: R E
authors: RE
authors: Baynes
authors: G W
authors: GW
authors: Smith
authors: J E
authors: JE
authors: Riviere
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003002:Clonixin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D008954:Models, Biological; D010599:Pharmacokinetics; D011485:Protein Binding; D013418:Sulfamethazine / Q000097:blood / Q000493:pharmacokinetics*; D013552:Swine / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D013418:Sulfamethazine; C014558:flunixin meglumine; D003002:Clonixin