Propuesta de una dosis de marbofloxacina para el tratamiento de infecciones asociadas a Escherichia coli en cabras de tres semanas de vida

Se estimó una dosis de marbofloxacina (MFX) para tratar infecciones gastrointestinales asociadas a Escherichia coli en cabras de tres semanas de vida. La farmacodinamia de MFX sobre E. coli se evaluó in vitro estimando las concentraciones inhibitoria mínima (CIM), bactericida mínima (CBM) y preventiva de mutantes (CPM). Marbofloxacina se administró en cabras de tres semanas de edad por vía subcutánea a una dosis de 2 mg/kg. Los parámetros farmacocinéticos se estimaron mediante análisis no compartimental. La dosis de MFX capaz de proteger al 95% de una población se calculó considerando la distribución poblacional de los parámetros farmacocinéticos. La eficacia de MFX se evaluó con la relación entre el área bajo la curva y la CPM (ABC/CPM) con un valor de corte de 22 h. Los resultados mostraron que la dosis estimada de MFX para alcanzar la remisión clínica de infecciones gastrointestinales causadas por E. coli y prevenir la emergencia de cepas resistentes en el 95% de una población de cabras de tres semanas de vida fue de 3,179 mg/kg, que a los fines prácticos se fijó en 3,5 mg/kg.

A dose of marbofloxacin (MFX) to treat gastrointestinal infections caused by Escherichia coli in 3-week-old goats was estimated. The pharmacodynamics of MFX against E. coli was evaluated in vitro by estimation of mínimum inhibitory concentration (MIC), mínimum bactericide concentration (MBC) and mutant prevention concentration (MPC). Marbofloxacin was administered to 3-week -old goats by subcutaneous route at the dose of 2 mg/kg. The pharmacokinetic parameters were estimated by non-compartmental analysis. The dose of MFX capable to protect the 95% of population was calculated considering the population distribution of pharmacokinetic parameters. The efficacy of MFX was evaluated by the relationship between the area under curve and MPC (AUC/MPC) with a cut-off value of 22 h. The results showed that the estimated dose of MFX to reach the clinical outcome of gastrointestinal infections caused by E. coli and to prevent the bacterial resistance at the 95% of the population of 3-week-old goats was 3.179 mg/kg, which for practical reasons was fixed at 3.5 mg/kg.

In-vitro Plasma Protein Binding of Marbofloxacin in Healthy and Disease Condition of Buffalo Calves

Marbofloxacin is a broad-spectrum fluoroquinolone antibiotic developed for use in veterinary medicine for the treatment of skin and soft tissue infections in dogs and cats. Plasma protein binding plays a vital role in distribution, elimination and therapeutic effectiveness of drugs. In the present study we evaluated the plasma protein binding of marbofloxacin in healthy and liver dysfunctioned buffalo calves. In vitro binding of marbofloxacin to plasma proteins was determined by employing the equilibrium dialysis technique and further analyzed by High Performance Liquid Chromatography assay. The plasma protein binding for healthy calves ranges between 25.3±0.34% to 30.4±0.40% with an overall binding of 28.66 ± 0.421%. Kinetic constants (βi) and (Kβ) was 2.6±0.12×10-8 mole/g and 1.9±0.08×10-7 mole, respectively. The percentage of plasma protein binding for liver dysfunctioned buffalo calves extended from 24.5 - 30.3% with an overall mean of 28.59 ± 0.693%. The binding capacity of the drug to plasma proteins (βi) and dissociation rate constant of protein drug complex (Kβ) were 2.53±0.13 10-5 mole/g and 1.94±0.09×10-6 mole respectively. There was no significant change observed in plasma protein binding and the kinetic constant of liver dysfunctioned buffalo calves when compared to the healthy group

Farmacocinética plasmática y urinaria de marbofloxacina intramuscular en caninos / Plasma and urine pharmacokinetics of intramuscular marbofloxacin in canines / Farmacocinética plasmática e urinária de marbofloxacina intramuscular em caninos

Resumen: Se estudió la disposición plasmática y urinaria de marbofloxacina en caninos (n = 6) tras la aplicación intramuscular de 2 mg/kg. En distintos tiempos posadministración se tomaron muestras de sangre hasta las 24 h, y de orina solo en los caninos machos (n = 4) a las 4, 8, 12 y 24 h. Se realizó una extracción líquido-líquido del analito con agua, metanol y centrifugado a 13.500 r. p. m. a 4 °C. La separación y cuantificación se realizó por HPLC mediante la elusión isocrática en fase reversa, utilizando columna C-18, detector de fluorescencia a 295 nm de excitación y 490 nm de emisión y fase móvil compuesta por agua, acetonitrilo y trietilamina. Las concentraciones plasmáticas temporales se analizaron con el software no compartimental PK Solution 2.0. Los resultados conseguidos indican pronta absorción, rápida y amplia distribución. El Cl y los valores conseguidos de t1/2β y TMR indican lenta depuración y prolongada permanencia. El ensayo determinó concentraciones plasmáticas perdurables hasta 24 h, y que exceden la CMI de patógenos relevantes. El cociente ABC/CMI indica eficacia frente a microorganismos con CMI ≤ 0,15 μg/ml. Las concentraciones urinarias de marbofloxacina son más significativas que las plasmáticas. No obstante, se requieren nuevos estudios que avalen su empleo con la dosis y vía de aplicación ensayada.

Abstract: Plasma and urinary disposition of marbofloxacin was studied in canines (n = 6) after intramuscular administration of 2 mg/kg. At different times post-administration, blood samples were collected until 24 h, and urine samples, only from male dogs (n = 4) at 4; 8; 12, and 24 h. Liquid-liquid extraction of analyte with water, methanol, and centrifugation at 13500 rpm at 4 °C were performed. Separation and quantification were made using HPLC by reverse phase isocratic elution with a C18 column, fluorescence detector at 295 nm excitation and 490 nm emission, and a mobile phase consisting of water, acetonitrile, and triethylamine. Temporary plasma concentrations were analyzed with non-compartmental PK Solution 2.0 software. The results obtained indicate rapid absorption, as well as rapid and wide distribution. Cl and values of t1/2β and MRT indicate slow clearance and prolonged stay. The study evidenced plasma concentrations up to 24 h, which exceed the MIC of relevant pathogens. The AUC/MIC ratio indicates efficacy against microorganisms with MIC ≤ 0.15 μg/ml. Urinary levels of marbofloxacin are more significant than plasmatic levels. However, new studies are required to assess their use with the tested dose and route of application.

Resumo: Se estudou a disposição plasmática e urinária de marbofloxacina em caninos (n = 6) após a aplicação intramuscular de 2 mg/kg. Em diferentes tempos pós-administração se tomaram amostras de sangue hasta as 24 h, e de urina somente nos caninos machos (n = 4) a as 4; 8; 12 e 24 h. Se realizou uma extração líquido-líquido do analito com água, metanol e centrifugado a 13500 r. p. m. a 4 °C. A separação e quantificação se realizou por HPLC mediante a eluição isocrática em fase reversa, utilizando coluna C-18, detector de fluorescencia a 295 nm de excitação e 490 nm de emissão e fase móvel composta por água, acetonitrilo e trietilamina. As concentrações plasmáticas temporárias se analisaram com o software não compartimental PK Solution 2.0. Os resultados conseguidos indicam pronta absorção, rápida e ampla distribuição. O Cl e os valores conseguidos de t1/2β e TMR indicam lenta depuração e prolongada permanência. O ensaio determinou concentrações plasmáticas perduráveis hasta 24 h, e que excedem a CMI de patógenos relevantes. O cociente ABC/CMI indica eficácia frente a micro-organismos com CMI ≤ 0,15 μg/ml. Os níveis urinários de marbofloxacina são mais significativos que os plasmáticos. Não obstante, se requerem novos estudos que avalizem seu uso com a dose e via de aplicação ensaiada.

Tissue distribution of marbofloxacin in pigs after a single intramuscular injection

Tissue distribution of marbofloxacin was studied in pigs after a single intramuscular injection at 2.5 mg/kg body weight. Samples of plasma, muscle, liver, kidney, heart, lung, and muscle at the injection site were randomly collected from five pigs at 2, 6, 10, 24, 48, 72, and 96 h after administration. Marbofloxacin concentrations were determined by using high-performance liquid chromatography with ultraviolet detection and were subjected to non-compartmental analysis to obtain kinetic parameters. The elimination half-life (t(1/2λz)) of marbofloxacin at the injection site was 22.12 h, while those in kidney, plasma, liver, lung, heart, and muscle were 16.75, 21.48, 21.84, 24.00, 24.45, and 28.91 h, respectively. Areas under the concentration-time curve from 0 h to (∞) (AUC(0–∞)s) were calculated to be 31.17 h·µg·mL⁻¹ for plasma and 32.97, 33.92, 34.78, 37.58, 42.02, and 98.80 h·µg·g⁻¹ for heart, muscle, lung, liver, kidney, and injection site, respectively. The peak concentration (C(max)) of marbofloxacin was 1.62 µg/mL in plasma and 1.71, 1.74, 1.86, 1.93, 2.45, and 7.64 µg/g in heart, lung, muscle, kidney, liver, and injection site, respectively. The results show that marbofloxacin was fast absorbed, extensively distributed, and slowly eliminated from pigs after a single intramuscular administration.