title: Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus).
abstract: Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted that extravascular routes of administration prolonged flunixin concentrations in milk, which could result in violative milk residues in treated cattle.
authors.affiliation: a Center for Chemical Toxicology Research and Pharmacokinetics, Department of Population Health and Pathobiology , College of Veterinary Medicine, North Carolina State University , Raleigh , NC , USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Leavens
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Tell
authors.forename: Lindsey W
authors.initials: LW
authors.lastname: Kissell
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Smith
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Wagner
authors.forename: Weilin L
authors.initials: WL
authors.lastname: Shelver
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Baynes
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002417:Cattle / Q000097:blood*; D003002:Clonixin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004350:Drug Residues; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008892:Milk / Q000737:chemistry; D008954:Models, Biological; D012680:Sensitivity and Specificity; D012984:Software; D035501:Uncertainty
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C014557:flunixin; D003002:Clonixin
keywords: PBPK models; cattle (Bos taurus); flunixin; route of administration; withdrawal intervals