Elsevier

Research in Veterinary Science

Volume 135, March 2021, Pages 293-296
Research in Veterinary Science

Pharmacokinetics and ex vivo pharmacodynamics of Minocycline against Salmonella abortus equi in donkey plasma and tissue cage fluid

https://doi.org/10.1016/j.rvsc.2020.10.003Get rights and content

Highlights

  • This study has demonstrated that MINO concentration exceeded the MIC for up to 24 h in plasma and 65 h in TCF.

  • The results suggested that MINO may prove to be therapeutically successful in treating infectious disease of donkey

  • Time-dependent characteristics needs to be confirmed in vivo PK/PD model and fractionation schedules.

  • These in vitro models will provide practical data that are much closer to the in vivo situation.

Abstract

Tissue Cage (TC) model was used to evaluate the pharmacokinetics and ex vivo pharmacodynamics of Minocycline (MINO) after intramuscular (IM) administration to donkeys at 4 mg/kg body-weight. The Cmax of MINO with 1.79 and 2.63 μg mL−1 was obtained at 2.96 and 1.41 h in TCF (tissue cage fluid) and plasma respectively. The absorption half-lives (t1/2ka) of MINO were calculated to be 0.71 h in TCF and 0.32 h in plasma, whereas the elimination half-lives (t1/2ke) were 10.46 h in TCF and 5.95 h in plasma. The distribution volume (Vd/F) of MINO was estimated to be 1.84 L kg−1 in TCF and 1.28 L kg−1 in plasma. The total clearance (CLb/F) of MINO was computed as 0.12 and 0.15 L/ (h·kg) in TCF and plasma respectively. The area under the concentration-time curve (AUC) of MINO was 32.77 μg mL−1h in TCF and 25.27 μg mL−1h in plasma, respectively.The ex vivo time-kill curves were established for plasma and TCF samples using Salmonella abortus equi. The MIC and MBC of MINO against salmonella were 0.08 and 0.16 μg mL−1 for plasma, 0.04 and 0.08 μg mL−1 for TCF. The plasma Cmax/MIC and AUC/MIC values after IM administration were 32.88 ± 9.87 and 315.88 ± 42.65 h, respectively. The TCF Cmax/MIC and AUC/MIC values after IM administration were 44.75 ± 9.32 and 819.25 ± 65.23 h, respectively. The values of T > MIC were approximately >36 h in plasma and > 65 h in TCF. These findings from this study suggest that MINO may be therapeutically effective in diseases of donkeys caused by salmonella when used at a dose of 4 mg/kg IM administration.

Introduction

The motivation to design more rational dosage regimens for antimicrobial drugs has been driven by increased knowledge of bacterial killing mechanisms, along with the results of laboratory animal research, target species investigations and clinical trial outcomes. During drugs development, in vitro and ex vivo assays provide a useful means of characterizing the concentration-effect profile of a given drug and for evaluating efficacy at the cellular and molecular level (Li et al. 2019; Perea, 2019).

Tissue cage (TC) was first used to study interstitial fluid physiology and composition (Zhang et al. 2019; Zhou et al. 2017). In the veterinary field, the TC model has been used to study the pharmacokinetic/pharmacodynamic (PK/PD) integration of antimicrobial drugs in some animals (Bhardwaj et al. 2019; Kang et al. 2019), including donkey.

Salmonella abortus equi is one of the most economically significant pathogens of donkey, and has a word-wide distribution (Wang et al. 2019). Salmonella abortus equi was isolated as the single agent and was responsible for the abortions. So far, there is limited information available on the PK/PD interaction of antibiotics against Salmonella abortus equi (ZHAO et al. 2018). Antimicrobial PK/PD analysis to identify the PD activity of antimicrobial agents through the integration of the PK properties and in vitro potency is one approach that has proven helpful to the design of effective dosing regimens in animals.

Many studies concerning PK/PD studies of antimicrobial against various species of bacteria have been reported (Poapolathep et al. 2019). It has been reported that bacteria have different growth behavior in vitro and in vivo, which particularly associated to the medium conditions and the source of substrates (Soudais et al. 2015). Bacteria grows differently between in TCs and in vitro. The bacteria could adhere to cells and fibers present in the matrix, which could make the the access of the drug more difficult in the vivo infection model. But vivo infection model really reflects the interaction between the body, drug and pathogens (Din et al. 2016; Jackson et al. 2016). Under these conditions, the aim of this study was to research the PK/PD profiles of MINO against Salmonella abortus equi in donkey by using vivo experimental infection model.

Minocycline (MINO) is one of the the most active broad-spectrum antibiotics of tetracyclines. Increased penetration of MINO into bacterial cells could result in high sensitivity against penicillinase-resistant strains of Staphylococcus aureus and a variety of other gram-positive and gram-negative organisms (Alfouzan et al., 2017; Chen et al. 2019). The increased accumulation of the drug within the cell is the primary advantage of MINO. It often used in the treatment of systemic infection of companion animals in the United States (Bayliss et al. 2019; Ito and Uemura 2016). At present, MINO has been studied less in veterinary medicine than the other tetracycline.

The aim of this study was to determine the PK and ex vivo PD characteristics of MINO for plasma and tissue cage fluid (TCF) after intramuscular (IM) administration to donkeys at a dose of 4 mg/kg. The ex vivo PD data and in vivo PK data were integrated and modelled for MINO as a basis for dosage determination.

Section snippets

Animals and experimental design

Eight healthy donkey (Dezhou donkey, 4males, 4females, 3 years old) were used for this study. Average body-weight (BW) was 100 kg. Each donkey received MINO at a dosage of 4 mg/kg BW by IM injection after TC had been implanted. The donkeys were housed and fed drug-free commercial diet twice a day and water was available. All animals remained in good health during the studies.

Tissue cage manufacture and implantation

TC was made in-house from platimum-cured medical grade silicone tubing (Medical silicon, SF medical) and modified

Pharmacokinetics of MINO in donkey plasma and TCF

MINO concentration in plasma and TCF are listed in Table 1; The plasma and TCF concentration-time profiles are illustrated in Fig. 1. The concentration-time (plasma and TCF) data in donkey conformed to absorption two-compartment open model. MINO was recovered in TCF between 0.083 and 72 h after IM administration. Pharmacokinetic parameters of MINO in donkey (plasma and TCF) obtained after IM administration with MINO at 4 mg/kg are shown in Table 2. The results showed that the absorption and

Discussion

In this study, the mean peak MINO concentration in TCF (1.79 μg mL−1)was significantly lower than the mean peak concentration in plasma (2.63 μg mL−1) after IM administration. However, the elimination half-times in TCF were much longer than in plasma (10.46 and 5.59 h). Theses results suggest that MINO may provide a good antibacterial effect in extra-vascular tissue.

Some studies have showed that MINO penetrated most tissue very well, much like other tetracycline (Yang et al. 2018), which is due

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

Acknowledgements

Shandong Modern Agricultural Product Technology System Donkey Innovation Team Project (SDAIT-27) and National Natural Science Foundation of China (No. 318725) sponsored this research.

References (22)

  • Q. Chen et al.

    Minocycline and silver dual-loaded polyphosphoester-based nanoparticles for treatment of resistant Pseudomonas aeruginosa

    Mol. Pharm.

    (2019)
  • View full text