Human Food Safety Implications of Variation in Food Animal Drug Metabolism

Abstract

Violative drug residues in animal-derived foods are a global food safety concern. The use of a fixed main metabolite to parent drug (M/D) ratio determined in healthy animals to establish drug tolerances and withdrawal times in diseased animals results in frequent residue violations in food-producing animals. We created a general physiologically based pharmacokinetic model for representative drugs (ceftiofur, enrofloxacin, flunixin, and sulfamethazine) in cattle and swine based on extensive published literature. Simulation results showed that the M/D ratio was not a fixed value, but a time-dependent range. Disease changed M/D ratios substantially and extended withdrawal times; these effects exhibited drug- and species-specificity. These results challenge the interpretation of violative residues based on the use of the M/D ratio to establish tolerances for metabolized drugs.

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

“…Berkeley Madonna (Version 8.3.23.0; University of California at Berkeley, CA, USA) was used to develop the PBPK models. Additional information for the PBPK model development can be found in our previous publications (Li et al, , ; Lin, Li, Gehring, & Riviere, ; Lin, Vahl, & Riviere, ). The model codes are provided in the and will also be deposited on our website (http://iccm.k-state.edu/).…”

“…The flow-limited model was applied for all tissue compartments in the current model based on the published model structure for penicillin G in beef cattle, market-age swine, and dairy cows Li, Gehring, Riviere, & Lin, 2018 Lin, Vahl, & Riviere, 2016). The model codes are provided in the Supporting Information and will also be deposited on our website (http://iccm.k-state.edu/).…”

Avoiding violative flunixin meglumine residues in cattle and swine

“…Also, the M/D is not a fixed value; it changes over time. 8 Those findings challenge the wisdom of regulatory policies that use a fixed M/D determined from a limited number of studies involving healthy animals to establish tolerances or MRLs because, in practice, drugs are generally not administered to healthy animals. 8 In a survey 45 of cull dairy cows performed at 21 US abattoirs between July 2003 and July 2004, the liver flunixin concentration was greater than the tolerance for 50 of 710 (7.04%) cows that appeared diseased, compared with only 2 of 251 (0.80%) cows that appeared healthy.…”

“…8 Those findings challenge the wisdom of regulatory policies that use a fixed M/D determined from a limited number of studies involving healthy animals to establish tolerances or MRLs because, in practice, drugs are generally not administered to healthy animals. 8 In a survey 45 of cull dairy cows performed at 21 US abattoirs between July 2003 and July 2004, the liver flunixin concentration was greater than the tolerance for 50 of 710 (7.04%) cows that appeared diseased, compared with only 2 of 251 (0.80%) cows that appeared healthy. In rats with experimentally induced acute liver or kidney disease that were treated with 1 dose of flunixin (2.2 mg/kg, IV), the apparent t 1/2 and total body clearance rate of flunixin were significantly longer, compared with those of control rats without experimentally induced liver or kidney disease.…”

Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach

“…Physiologically based pharmacokinetic (PBPK) and nonlinear mixed-effects pharmacokinetic (NLME-PK) models are helpful tools in the establishment of withdrawal time guidelines for veterinary drugs [5–7]. Currently, there are pharmacokinetic data for tulathromycin in the plasma and tissues of juvenile and market-age goats after single or multiple intravenous (IV), intramuscular (IM), or subcutaneous (SC) injections [3, 8, 9].…”