Tardiveau J.(1,2), Touchais G.(3), Chotard-Soutif M.P.(3), Laurentie M.(3), Paraud C.(4), Mirfendereski H.(1,5), Marchand S.(1,2,6), Alexis V.(3), Grégoire N.(1,2,6)
(1) INSERM U1070, University of Poitiers, France , (2) Medical-pharmacy faculty, University of Poitiers, France, (3) Anses, Fougères Laboratory, Fougères, France, (4) Anses, Niort-Ploufragan-Plouzané Laboratory, Niort, France, (5) University Hospital Center of Poitiers, France, (6) Toxicology-Pharmacokinetic department, University Hospital Center of Poitiers, France
Objectives: The presence of antibiotic residues in the milk of farm animals can have an impact on human health, in particular by favouring the emergence of resistance among the bacteria of the consumers’ intestinal microbiota.[1]. The excretion of antibiotic towards milk depends on several factors as physicochemical properties of the drug (ionization, lipophilicity, protein binding), organism (species, lactation period) and milk composition (fat, proteins, ions) [2][3]. The aim of this study was to use Physiologically Based Pharmacokinetic (PBPK) modeling, considering the aforementioned factors and the animal’s physiology, to predict oxytetracycline (OTC) residues in milk of cows and goats.
Methods: OTC was administered intramuscularly at 10 mg.kg-1 in single dose to lactating goats and cows (n=6 each). Plasma samples were collected for two days and milk samples for five days. Samples were assayed by HPLC-UV and LC-MS/MS for plasma and milk, respectively. The limits of quantification were 0.05 and 0.02 µg/ml in plasma and milk, respectively. Milk volume was measured at each milking. The PBPK model was developed using Monolix®[4]. OTC chemical and pharmacokinetic properties and both species’ physiology parameters used in the PBPK model were found in the literature. The udder compartment was divided into sub-compartments: extracellular water (EW), intracellular water (IW) and milk, which was stored in alveolar and cistern compartments [5][6]. We have assumed that the OTC binds to albumin in EW; to neutral lipids, neutral phospholipids, and acidic phospholipids in IW as well as to fat, casein, whey proteins and free ionized calcium and magnesium contained in milk. We considered that not all the milk was collected at each milking but that a fraction remained in the udder. This fraction depends on the species and the milking interval. [7][8]. We have assumed that OTC is not actively transported, a bidirectional passive diffusion across the blood-milk barrier was considered, based on in vitro permeability studies [9]. For physiological and chemical-specific parameters obtained in the literature, inter-individual variability were fixed to 20% and 30%, respectively [10]. Residual error was estimated based on intermediary precision of analytical method. The experimental data were used to validate the PBPK model, by overlaying them with the 90% prediction interval.
Results: OTC was quantified in milk up to 4 days after administration for both species. 0.8% and 0.5% of administered dose was excreted in milk of cows and goats, respectively. The observed concentrations were within the 90% prediction interval, for both species, thus validating the model [11].
Conclusions: The developed PBPK model succeeded in characterizing the OTC excretion into the milk of two species. This model can be used to predict the waiting times of OTC in cow and goat milk but can also be extrapolated to other drugs or other animal species, such as ewes, or even to women. For this purpose, the inclusion of active transport might be necessary.
References:
[1] M. Li, R. Gehring, J. E. Riviere, and Z. Lin, “Probabilistic Physiologically Based Pharmacokinetic Model for Penicillin G in Milk From Dairy Cows Following Intramammary or Intramuscular Administrations,” Toxicological Sciences, vol. 164, no. 1, pp. 85–100, Jul. 2018, doi: 10.1093/toxsci/kfy067.
[2] Z. Ozdemir, “Behaviours of Drugs in the Milk -A Review,” Atatürk Üniversitesi Vet. Bil. Derg., Accessed: Jan. 08, 2020. [Online]. Available: https://www.academia.edu/38701395/Behaviours_of_Drugs_in_the_Milk_-A_Review
[3] N. Shappell, W. Shelver, S. Lupton, W. Fanaselle, J. Doren, and H. Hakk, “Distribution of Animal Drugs among Curd, Whey, and Milk Protein Fractions in Spiked Skim Milk and Whey,” Journal of Agricultural and Food Chemistry, vol. 65, Jan. 2017, doi: 10.1021/acs.jafc.6b04258.
[4] cdw-admin, “Monolix,” Lixoft. https://lixoft.com/products/monolix/ (accessed Feb. 18, 2021).
[5] T. Rodgers, D. Leahy, and M. Rowland, “Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases,” J Pharm Sci, vol. 94, no. 6, pp. 1259–1276, Jun. 2005, doi: 10.1002/jps.20322.
[6] M. Jamei et al., “A Mechanistic Framework for In Vitro–In Vivo Extrapolation of Liver Membrane Transporters: Prediction of Drug–Drug Interaction Between Rosuvastatin and Cyclosporine,” Clin Pharmacokinet, vol. 53, no. 1, pp. 73–87, Jan. 2014, doi: 10.1007/s40262-013-0097-y.
[7] T. Whittem, J. H. Whittem, and P. D. Constable, “Modelling the concentration–time relationship in milk from cattle administered an intramammary drug,” Journal of Veterinary Pharmacology and Therapeutics, vol. 35, no. 5, pp. 460–471, 2012, doi: 10.1111/j.1365-2885.2011.01352.x.
[8] M. Peaker and D. R. Blatchford, “Distribution of milk in the goat mammary gland and its relation to the rate and control of milk secretion,” Journal of Dairy Research, vol. 55, no. 1, pp. 41–48, Feb. 1988, doi: 10.1017/S0022029900025838.
[9] M. Fujikawa, R. Ano, K. Nakao, R. Shimizu, and M. Akamatsu, “Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes: Application to prediction of Caco-2 cell permeability,” Bioorganic & Medicinal Chemistry, vol. 13, no. 15, pp. 4721–4732, Aug. 2005, doi: 10.1016/j.bmc.2005.04.076.
[10] M. Li et al., “Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration,” Arch Toxicol, Apr. 2019, doi: 10.1007/s00204-019-02464-z.
[11] Weltgesundheitsorganisation, International Programme on Chemical Safety, and Inter-Organization Programme for the Sound Management of Chemicals, Eds., Characterization and application of physiologically based pharmacokinetic models in risk assessment. Geneva: World Health Organization, 2010.
Reference: PAGE 29 (2021) Abstr 9772 [www.page-meeting.org/?abstract=9772]
Poster: Drug/Disease Modelling - Absorption & PBPK