Doxycycline serum protein binding in pigs reveals a relatively high free fraction

Felipe Ramon, Portugal; Marlène Z., Lacroix; Béatrice B., Roques; Véronique, Gayrard; Pierre-Louis, Toutain; Bousquet-Mélou, Alain

Abstract

Doxycycline is an antibiotic widely used in pig farming, which leads to update the doses using PK/PD concepts. However, there is an impasse to estimate the PK/PD cut-off of doxycycline in pigs. Indeed, considering its 7% free fraction and the total steady state concentrations reported in pig plasma (0.35-1.5 µg/mL), the estimated free concentrations of doxycycline (0.025-0.15 µg/mL) are far lower than the tetracycline MIC50 reported for P. multocida (MIC50 = 0.5 µg/mL). This apparent discrepancy may be explained by the atypical and counter-intuitive non-linear binding of tetracyclines to serum proteins. Plasma protein binding is usually determined by pooling plasma from healthy animals, this does not take into account the inter-subject variability required to define a PK/PD cut-off.
Thus, the protein binding was determined by equilibrium dialysis using individual plasma from twenty-six pigs at doxycycline concentration ranging from 1 to 1000 µM. This study investigated both the shape and measurement of doxycycline protein binding and estimated inter-subject variability using a non-linear mixed effects model.
Our results did not indicate any “atypical” protein binding and reveals a higher free fraction of doxycycline in pig plasma than previously reported (~31%) with a relatively low between-subject variability (~10%).

Citation

Felipe Ramon, P., Marlène Z., L., Béatrice B., R., Véronique, G., Pierre-Louis, T., & Bousquet-Mélou, A. (2023). Doxycycline serum protein binding in pigs reveals a relatively high free fraction. Journal of Veterinary Pharmacology and Therapeutics, https://doi.org/10.1111/jvp.13111

• Journal Article Type: Article
• Acceptance Date: Dec 13, 2022
• Publication Date: Jan 24, 2023
• Deposit Date: Jan 3, 2023
• Publicly Available Date: Jan 25, 2024
• Journal: JVPT
• Print ISSN: 0140-7783
• Publisher: American Academy of Veterinary Pharmacology and Therapeutics
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1111/jvp.13111