Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.

Disposition of a long-acting oxytetracycline formulation in Thai swamp buffaloes (Bubalus bubalis).

The present study aimed to characterize the pharmacokinetic profile of oxytetracycline long-acting formulation (OTC-LA) in Thai swamp buffaloes, Bubalus bubalis, following single intramuscular administration at two dosages of 20 and 30 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 504 h. The plasma concentrations of OTC were measured by high-performance liquid chromatography (HPLC). The concentrations of OTC in the plasma were determined up to 264 h and 432 h after i.m. administration at doses of 20 and 30 mg/kg b.w., respectively. The Cmax values of OTC were 12.11 ± 1.87 µg/mL and 12.27 ± 1.92 µg/mL at doses of 20 and 30 mg/kg, respectively. The AUClast values increased in a dose-dependent fashion. The half-life values were 52.00 ± 14.26 h and 66.80 ± 10.91 h at doses of 20 and 30 mg/kg b.w, respectively. Based on the pharmacokinetic data and PK-PD index (T > MIC), i.m. administration of OTC at a dose of 30 mg/kg b.w once per week might be appropriate for the treatment of susceptible bacterial infection in Thai swamp buffaloes.

Correlation between oral fluid and plasma oxytetracycline concentrations after intramuscular administration in pigs.

The penetration of oxytetracycline (OTC) into the oral fluid and plasma of pigs and correlation between oral fluid and plasma were evaluated after a single intramuscular (i.m.) dose of 20 mg/kg body weight of long-acting formulation. The OTC was detectable both in oral fluid and plasma from 1 hr up to 21 day after drug administration. The maximum concentrations (Cmax ) of drug with values of 4021 ± 836 ng/ml in oral fluid and 4447 ± 735 ng/ml in plasma were reached (Tmax ) at 2 and 1 hr after drug administration respectively. The area under concentration-time curve (AUC), mean residence time (MRT) and the elimination half-life (t1/2ß ) were, respectively, 75613 ng × hr/ml, 62.8 hr and 117 hr in oral fluid and 115314 ng × hr/ml, 31.4 hr and 59.2 hr in plasma. The OTC concentrations were remained higher in plasma for 48 hr. After this time, OTC reached greater level in oral fluid. The strong correlation (r = .92) between oral fluid and plasma OTC concentrations was observed. Concentrations of OTC were within the therapeutic levels for most sensitive micro-organism in pigs (above MIC values) for 48 hr after drug administration, both in the plasma and in oral fluid.

Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration.

Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.

Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens.

Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens.

Effect of body size on the oral pharmacokinetics of oxytetracycline in rainbow trout (Oncorhynchus mykiss).

Objective: The aim of this study was to determine the plasma pharmacokinetics of oxytetracycline (OTC) in rainbow trout (Oncorhynchus mykiss) of different body sizes. Methods: The research was carried out on three groups as small (30-50 g), medium (90-110 g) and large (185-215 g) body sizes at 8 ± 0.5 °C. OTC was administered orally at a dose of 60 mg/kg to all groups. Blood samples were taken at 19 different sampling times until the 384 h after oxytetracycline administration. The plasma concentrations of OTC were measured using high pressure liquid chromatography-ultraviolet and pharmacokinetic parameters were evaluated using non-compartmental analysis. Results: OTC was detected in small-body sized fish until the 336 h and in medium and large-body sized fish until the 384 h. The elimination half-life of OTC was 85.46, 87.24 and 86.98 h in the small, medium and large body size groups, respectively. The peak plasma concentration increased from 0.66 to 1.11 µg/mL, and the area under the plasma concentration-versus time curve from zero (0) h to infinity (∞) increased from 87.86 to 151.52 h*µg/mL, in tandem with the increase in fish body size. As fish body size increased, volume of distribution and total body clearance decreased. Conclusion: These results show that the pharmacokinetics of OTC vary depending on fish size. Therefore, there is a need to reveal the pharmacodynamic activity of OTC in rainbow trout of different body sizes.

Pharmacokinetics of oxytetracycline in hybrid catfish (Clarias macrocephalus x C. gariepinus) after intravascular and oral administrations.

IMPORTANCE: Over the past decade, catfish farming has increased in Southeast Asia. However, there has been no existing for pharmacokinetic data in the hybrid catfish (Clarias macrocephalus x C. gariepinus). OBJECTIVE: This study was designed to evaluate the pharmacokinetic characteristics of oxytetracycline (OTC) in the hybrid catfish, following single intravascular (IV) or oral (PO) administration at a single dosage of 50 mg/kg body weight (BW). METHODS: In total, 140 catfish (each about 100-120 g BW) were divided into two groups (n = 70). Blood samples (0.6-0.8 mL) were collected from ventral caudal vein at pre-assigned times up to 144 h (sparse samples design). OTC plasma concentrations were analyzed using high-performance liquid chromatography-photodiode array detector. RESULTS: The pharmacokinetic parameter of OTC was evaluated using a non-compartment model. OTC plasma concentrations were detectable for up to 144 and 120 h after IV and PO, respectively. The elimination half-life value of OTC was long with slow clearance after IV administration in hybrid catfish. The average maximum concentration value of OTC was 2.72 µg/mL with a time at the maximum concentration of 8 h. The absolute PO bioavailability was low (2.47%). CONCLUSIONS AND RELEVANCE: These results showed that PO administration of OTC at a dosage of 50 mg/kg BW was unlikely to be effective for clinical use in catfish. The pharmacodynamic properties and clinical efficacy of OTC after multiple medicated feed are warranted.

An electrochemical biosensor for the direct detection of oxytetracycline in mouse blood serum and urine.

Oxytetracycline (OTC), a broad-spectrum antibiotic, has been extensively used as a food additive for livestock. Its extensive use has greatly increased the risk of chronic drug abuse and has also increased the risk of the resulting diseases. Therefore, in light of this emerging situation, the detection of OTC in both food and livestock is very important to reduce the risks and for diagnosis purposes . In this work, we have proposed an electrochemical aptasensor to quantify OTC. The biosensor shows considerable sensitivity and selectivity, and it can be easily operated and regenerated. Furthermore, for the first time, we have shown that an electrochemical aptasensor can be directly used to detect OTC in mouse blood serum and urine. This biosensor has the potential to aid in the analysis of residual OTC levels, as well as providing more pharmacokinetic information in the future.

Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves.

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 µg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.

A physiologically based pharmacokinetic (PBPK) model exploring the blood-milk barrier in lactating species - A case study with oxytetracycline administered to dairy cows and goats.

Antibiotic excretion into milk depends on several factors such as the compound's physicochemical properties, the animal physiology, and the milk composition. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the passage of drugs into the milk of lactating species. The udder is described as a permeability limited compartment, divided into vascular, extracellular water (EW), intracellular water (IW) and milk, which was stored in alveolar and cistern compartments. The pH and ionization in each compartment and the binding to IW components and to milk fat, casein, whey protein, calcium, and magnesium were considered. Bidirectional passive diffusion across the blood-milk barrier was implemented, based on in vitro permeability studies. The model application used to predict the distribution of oxytetracycline in cow and goat milk, after different doses and routes of administration, was successful. By integrating inter-individual variability and uncertainty, the model also allowed a suitable estimation of the withdrawal periods. Further work is in progress to evaluate the predictive ability of the PBPK model for compounds with different physico-chemical properties that are potentially actively transported in order to extrapolate the excretion of xenobiotics in milk of various animal species including humans.

Penetration of oxytetracycline into the nasal secretions and relationship between nasal secretions and plasma oxytetracycline concentrations after oral and intramuscular administration in healthy pigs.

The penetration of oxytetracycline (OTC) in plasma and nasal secretions of healthy pigs was evaluated during the first study, in response to oral dose of 20 mg of OTC per kg of body weight (bwt) per day as a 400 mg/kg feed medication (n = 5) and to intramuscular (i.m.)-administered formulations at 10 mg/kg bwt (n = 5), 20 mg/kg bwt (n = 5), 40 mg/kg bwt (n = 5). Concentrations of OTC in plasma and nasal secretions were determined by a validated ultra-high performance liquid chromatography associated to tandem mass spectrometry method (UPLC/MS/MS). The objectives were to select the efficacy treatment and to evaluate the possibility to predict nasal secretions concentrations from those determined in plasma. The animals were housed together in each experiment. In each group, the treatment was administered once daily during 6 consecutive days, and nasal secretions and plasma were collected after 4 and 24 h at day 2 and day 6. For oral administration, only one medicated feed was prepared and distributed to all the animals together and was consumed in approximately 1 h. To meet recommendations of efficacy for OTC in nasal secretions, only the i.m. of 40 mg/kg bwt associated to an inter-dosing interval of 24 h provides and maintains concentrations in nasal secretions ≥1 µg/mL, appropriate to the MIC 50 and 90 of Pasteurella multocida and Bordetella bronchiseptica, respectively, the main pathological strains in nasal secretions. It has been demonstrated that, using a generalized linear mixed model (GLMM), OTC in the nasal secretions (µg/mL) can be predicted taking into account the OTC concentrations in plasma (µg/mL), according to the following equation: OTC(nasal secretions) = 0.28 OTC(plasma) -1.49. In a second study, the pharmacokinetic behaviour of OTC in plasma and nasal secretions of healthy pigs was investigated, after single-dose i.m. of 40 mg/kg bwt of the drug. Blood samples and nasal secretions were collected at predetermined times after drug administration. The data collected in 10 pigs for OTC were subjected to non-compartmental analysis. In plasma, the maximum concentration of drug (C(max) ), the time at which this maximum concentration of drug (T(max) ) was reached, the elimination half-life (t½) and the area under the concentration vs. time curve (AUC) were, respectively, 19.4 µg/mL, 4.0, 5.1 h and 150 µg·h/mL. In nasal secretions, C(max) , T(max) , t½ and AUC were, respectively, 6.29 µg/mL, 4.0, 6.6 h and 51.1 µg·h/mL.

Developing a High-Performance Liquid Chromatography (HPLC) Method for Simultaneous Determination of Oxytetracycline, Tinidazole and Esomeprazole in Human Plasma.

A high performance liquid chromatography method had been developed and validated for rapid simultaneous separation and determination of three anti-helicobacter drugs, oxytetracycline (OXY), tinidazole (TIN) and esomeprazole (ESM) in human plasma within 6 minutes. Drugs extraction method from plasma was based on protein precipitation technique. Separation was carried out on a Equisil BDS C18 column (5 µm, 150 × 4.60 mm) using a mobile phase of acetonitrile: 0.025 M KH2PO4 (25: 75, v/v) adjusted to pH 3.50 with ortho-phosphoric acid at ambient temperature. The flow rate was 1 mL/min and maximum absorption was measured using Diode Array (DAD) detector at 285 nm. The retention times of OXY, TIN and ESM were recorded to be 2.68, 3.52 and 5.17 minutes, respectively, indicating a shorter analysis time. Limits of detection were also reported to be 0.10, 0.07 and 0.04 µg/mL for OXY, TIN and ESM, respectively, showing a high degree of the method sensitivity. The method was then validated according to FDA guidelines for the determination of the drugs clinically in human plasma specially regarding pharmacokinetic and bioequivalence studies.

Hard water may increase the inhibitory effect of feed on the oral bioavailability of oxytetracycline in broiler chickens.

The aim of this study was to determine to what extent the ions present in hard water (125 mg/L of MgCl2 and 500 mg/L of CaCl2) may intensify the feed-induced decrease in oxytetracycline (OTC) absorption rate in broiler chickens after single oral administration at a dose of 15 mg/kg. Drug concentrations in plasma were determined by liquid chromatography-tandem mass spectrometry and combined, compartmental and non-compartmental approach was used to assess OTC pharmacokinetics. The administration of feed decreased the absolute bioavailability (F) of OTC from 12.70%±4.01 to 6.40%±1.08, and this effect was more pronounced after the combined administration of OTC with feed and hard water (5.31%±0.90). A decrease in the area under the concentration- time curve (AUC0-t), (from 10.18±3.24 µg·h/ml in control to 5.13 µg·h/ml±1.26 for feed and 4.26 µg·h/ml±1.10 for feed and hard water) and the maximum plasma concentration of OTC (Cmax) (from 1.22±0.18 µg/ml in control, to 1.01 µg/ml ±0.10 for hard water, 0.68 µg/ml±0.10 for feed and 0.61 µg/ml±0.10 for feed and hard water) was observed. The results of this study indicate that feed strongly decreases F, AUC0-t and Cmax of orally administered OTC. The ions present in hard water increase this inhibitory effect, which suggests that, therapy with OTC may require taking into account local water quality and dose modification, particularly when dealing with outbreaks caused by less sensitive microorganisms.

Is the current dose of a conventional oxytetracycline formulation adequate for the management of infections in sheep?

In the veterinary industry, short-acting or conventional oxytetracycline formulations are recommended for use once a day for 4 days, at a dose of 10 mg/kg. With the large degree of antimicrobial resistance reported, the efficacy of this dose was assessed using pharmacodynamic modelling. The specific parameters evaluated were based on the time-dependent activity of the tetracycline class of antimicrobials according to the total time above minimal inhibitory concentration (T > MIC) and the ratio of the total exposure in 24 hours, represented by area under the curve (AUC24), to the minimal inhibitory concentration (AUC24:MIC). The current pharmacokinetic study examined whether the prevailing antimicrobial resistance could be overcome by doubling the recommended conventional dose. Using reported MIC data for South Africa and elsewhere, modelling indicated the presence of a large degree of resistance. In general, doubling the dose only overcame resistance of 2 bacterial species in South Africa.

Determination of oxytetracycline levels in rainbow trout serum on a biphenyl column using high-performance liquid chromatography.

We developed a simple and sensitive high-performance liquid chromatography method on a biphenyl column to determine oxytetracycline (OTC) levels in rainbow trout serum. The assay used deproteination, filtration, and subsequent separation on a reverse-phase biphenyl column, with UV detection at 355 nm. OTC (7.8-7.9 min) was completely resolved from structurally similar riboflavin (10.4-10.5 min), a common feed supplement. Estimated limits of detection and quantitation of OTC were 0.01 and 0.04 microg/mL, respectively. The average recovery for OTC was 102% with a R.S.D. of 8.34%. Calibration standards were linear from 0.01 to 10 microg/mL.

Pharmacokinetics and tissue residues of an oxytetracycline/diclofenac combination in cattle.

Eight male cattle were given a combined dose containing 20 mg/kg oxytetracycline and 0.5 mg/kg diclofenac intramuscularly. Blood samples were drawn at different times until 168 h after administration. Two experimental animals were slaughtered by humane means at weekly intervals up to 28 days after administration. Samples of muscle, injection zone tissue, liver, kidney and fat were obtained. Oxytetracycline and diclofenac concentrations were determined by high performance liquid chromatography. Kinetic analysis was performed by linear regression using the CSTRIP programme. Plasma oxytetracycline concentration showed a maximum (Cmax) of 3.89 +/- 1.48 microg/ml and a prolonged elimination half-life (T1/2beta: 47.73 +/- 18.33 h). The diclofenac plasma profile showed high Cmax (577.62 +/- 238.40 ng/ml), and its T1/2beta was also prolonged (30.48 +/- 9.42 h). Oxytetracycline concentrations were measurable in liver and adipose tissue until day 21 after administration, but all tissue samples were negative for diclofenac at 21 days. The long elimination half-life of diclofenac was an unexpected finding; its T1/2beta in humans is 1.1 h.

Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models From acslX to Berkeley Madonna, MATLAB, and R Language: Oxytetracycline and Gold Nanoparticles As Case Examples.

Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslX. However, acslX has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of 4 PBPK modeling software packages (acslX, Berkeley Madonna, MATLAB, and R language) tested using 2 existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslX to Berkeley Madonna, MATLAB, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field. Simulation results of plasma/tissue concentrations/amounts of oxytetracycline and gold from different models were compared visually and statistically with linear regression analyses. Simulation results from the original models were correlated well with results from the recoded models, with time-concentration/amount curves nearly superimposable and determination coefficients of 0.86-1.00. Step-by-step explanations of the recoding of the models in different software programs are provided in the Supplementary Data. In summary, this article presents a tutorial of PBPK model code conversion for a small molecule and a nanoparticle among 4 software packages, and a performance comparison of these software packages in PBPK model implementation. This tutorial helps beginners learn PBPK modeling, provides suggestions for selecting a suitable tool for future projects, and may lead to the transition from acslX to alternative modeling tools.

Bioequivalence study of two long-acting oxytetracycline formulations in sheep.

Two commercially available long-acting oxytetracycline hydrochloride formulations (Primamycin LA (Pfizer) and Terralent 20% LA (I.E. Ulagay)) were administered by the intramuscular route to 20 clinically healthy sheep at a dose of 20 mg/kg. The study was performed in a two-period crossover design. Plasma samples were analysed by high-pressure liquid chromatography. The mean maximum concentrations (C (max)) was 8.00 +/- 2.05 microg/ml and 8.61 +/- 1.42 micro/ml, respectively. The mean area under the concentration time curve (AUC) values were 154.95 +/- 50.37(microg h)/ml and 161.70 +/- 47.02(microg h)/ml, respectively. The 90%confidence intervals for the ratio of C (max) and AUC values for the test and reference product are with in the interval 70-143% for C (max) and interval 80--125% for AUC proposed by EMEA. It was concluded that Primamycin LA and Terralent 20% LA formulations are bioequivalent in their rate and extent of drug absorbtion.

Metal ion-oxytetracycline pharmacokinetic interactions after oral co-administration in broiler chickens.

The influence of the composition of calcium (Ca(2+)), magnesium (Mg(2+)), and iron (Fe(3+)) ions in two concentration levels (low-500 mg/L of CaCl2, 125 mg/L of MgCl2, and 10 mg/L of FeCl3 and high-2,500 mg/L of CaCl2, 625 mg/L of MgCl2, and 50 mg/L of FeCl3) contained in water on the pharmacokinetics (PK) of oxytetracycline (OTC) was determined. OTC hydrochloride was administered at a dose of 25 mg/kg of body weight to broiler chickens divided into four groups of nine birds each, including 3 oral groups (in deionized water -control, in water with low ion concentration, and in water with high ion concentration) and 1 intravenous group. OTC concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry, after which non-compartmental pharmacokinetic analysis was conducted.The absolute bioavailability of OTC in the group of birds exposed to higher ions concentration was reduced (8.68% ± 2.56) as compared to the control (13.71% ± 2.60). Additionally, in this group, decrease in PK parameters such as: area under the concentration-time curve from 0 to infinity (15.36 µg × h/mL ± 4.36), from 0 to t (14.78 µg × h/mL ± 4.37), area under the first moment of curve from 0 to t (107.54 µg × h/mL ± 36.48), and maximum plasma concentration (2.13 µg/mL ± 0.32) were also observed. It is noteworthy, all mentioned parameters demonstrated a downward trend with high correlation coefficient (P = 0.004, P = 0.002, P = 0.005, P = 0.004, P = 0.011, respectively), reflecting the influence of increasing concentrations of Ca(2+), Mg(2+), and Fe(3+) ions on the decreasing absorption rate of OTC.Based on the current research results, it can be assumed that high concentrations of several ions applied concomitantly are able to decrease the absorption of OTC from gastrointestinal tract in broiler chickens. This occurrence might impair the drug's clinical efficacy toward some pathogenic microorganisms. It implies that using OTC on a farm may require administration of higher doses than the routine one when infections are caused by less sensitive pathogens.

Impact of 4-epi-oxytetracycline on the gut microbiota and blood metabolomics of Wistar rats.

The impact of 4-epi-oxytetracycline (4-EOTC), one of the main oxytetracycline (OTC) metabolites, on the gut microbiota and physiological metabolism of Wistar rats was analyzed to explore the dynamic alterations apparent after repeated oral exposure (0.5, 5.0 or 50.0 mg/kg bw) for 15 days as shown by 16S rRNA pyrosequencing and UPLC-Q-TOF/MS analysis. Both principal component analysis and cluster analysis showed consistently altered patterns with distinct differences in the treated groups versus the control groups. 4-EOTC treatment at 5.0 or 50.0 mg/kg increased the relative abundance of the Actinobacteria, specifically Bifidobacteriaceae, and improved the synthesis of lysophosphatidylcholine (LysoPC), as shown by the lipid biomarkers LysoPC(16:0), LysoPC(18:3), LysoPC(20:3), and LysoPC(20:4). The metabolomic analysis of urine samples also identified four other decreased metabolites: diacylglycerol, sphingomyelin, triacylglycerol, and phosphatidylglycerol. Notably, the significant changes observed in these biomarkers demonstrated the ongoing disorder induced by 4-EOTC. Blood and urine analysis revealed that residual 4-EOTC accumulated in the rats, even two weeks after oral 4-EOTC administration, ceased. Thus, through thorough analysis, it can be concluded that the alteration of the gut microbiota and disorders in blood metabolomics are correlated with 4-EOTC treatment.