Browsing by Subject "Pharmacokinetics"
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- PublicationOpen AccessBioequivalence study of lumefantrine rectal enema and the commercially available generic oral suspension. A pilot study(Society of Pharmaceutical Sciences and Research (SPSR), 2024-05-01) Mhango, E. K. G.; Marín, P.; Escudero, E.; Yuste Pérez, María Teresa; Eiriksson, F. F.; Snorradottir, B. S.; Sveinbjornsson, B. R.; Gizurarson, S.; FarmacologíaChildren under five years of age, with severe or cerebral malaria, cannot consume oral medication especially if they are vomiting or are unconscious. In such situations they are given an injectable drug until they can tolerate oral medication. The situation is bad in Sub-Saharan Africa, especially in rural areas as children are sometimes referred to the closest referral health care facility for proper management. The aim of this study was therefore to conduct a pilot study to estimate the bioavailability of lumefantrine (LF) when administered as a rectal enema, and compare it with a commercially available oral suspension, in rabbits. The study was conducted on six healthy rabbits in an open randomized, crossover three sequence, single dose study, where each rabbit received rectal and oral formulations. The oral formulation was administered under fed and fasted conditions. A two-week washout period was allowed between the experiments. LF was quantified in rabbit plasma using ultraperformance liquid chromatography tandem mass spectrometry (UPLC MS/MS). Results showed that the relative bioavailability of rectal LF was about four times higher than oral. The observed data suggest that a significant adjustment in the dose will be required when LF is administered via the rectal route. The data provide important information for the next step in finding a method to provide a rescue treatment for children with severe or cerebral malaria.
- PublicationOpen AccessDisposition kinetics and bioavailability of doxycycline after parenteral administrations in ewes(Elsevier, 2024-09-10) Martínez, José; Escudero Pastor, Elisa; Badillo Puerta, Elena; Yuste Pérez, María Teresa; Galecio Naranjo, Juan Sebastian; Marín Carrillo, Pedro; FarmacologíaDoxycycline is a tetracycline, which have been marketed in different species for treating infections caused by susceptible bacteria. There is limited information on the disposition kinetics of this drug in ewes and this antimicrobial may be useful against several sheep pathogens that are common causes of morbidity and economic loss. Therefore, the aim of this work was to establish the pharmacokinetics of doxycycline after intravenous (IV) and extravascular (subcutaneous (SC) and intramuscular (IM)) administrations in this species. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for IV administration and 20 mg/kg for extravascular administrations. Non-compartmental pharmacokinetic methods were used to calculate plasma concentration-time data. The value of apparent volume of distribution (Vz) suggests a moderate distribution of this antibiotic in sheep, with a value of 0.84 L/kg. The maximum concentrations achieved after extravascular administrations (Cmax) were similar, with no significant differences between the two routes of administration (IM and SC). However, doxycycline absorption was slower after SC administration than after IM administration, taking twice as long to reach maximum plasma concentration (tmax). Bioavailabilities after extravascular routes of administration were low and after IM administration doxycycline caused lameness in all animals. Therefore, the SC administration showed a better profile with respect to pharmacokinetic properties and safety. Future studies on the susceptibility of isolated sheep pathogens to doxycycline are needed to establish appropriate dosing regimens.
- PublicationOpen AccessDisposition kinetics of tildipirosin in alpacas after parenteral administrations(Elsevier, 2023-11-10) Galecio, Juan Sebastian; Escudero, Elisa; Egas, David; Mena, Luis; Badillo Puerta, Elena; Marin, Pedro; Hernandis, Verónica; FarmacologíaTildipirosin is a macrolide antibiotic marketed in veterinary medicine to treat respiratory infections in pigs and calves. There are no pharmacokinetics studies of tildipirosin after parenteral administration in alpacas which is an extremely decisive step for determining dosage regimen. Thus, the aim of the present study was to establish the disposition fate of tildipirosin following intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations in alpacas. A crossover study was used, and each alpaca received a single dose of tildipirosin by IV and IM or SC. All the routes of administration were adequately tolerated, and no adverse reactions was observed in any alpaca. Tildipirosin in alpacas reached peak concentrations (Cmax = 0.68 µg/mL vs. 0.79 µg/mL) at 0.22 and 0.50 h (tmax) after IM and SC administration, respectively, with an absolute bioavailability of >100 % for both routes of administration. Steady-state volume of distribution and clearance were 6.02 ± 1.34 L/kg and 2.76 ± 0.28 L/h/kg, respectively. Tildipirosin presents a particular pharmacokinetic behaviour in alpacas, distinctive from other ruminant species, confirming the need to perform studies in the target species in order to promote rational dose regimens of this antimicrobial to maximize its efficacy, minimize its toxicity and avoid the emergence of resistant bacteria.
- PublicationOpen AccessEmpleo del cannabidiol (CBD) en la osteoartrosis canina(Facultad de Veterinaria y el Servicio de Publicaciones de la Universidad de Murcia, 2023-12-29) Lara Herrera, Víctor; Cárceles Rodríguez, Carlos; Farmacología; Facultad de VeterinariaLa planta Cannabis sativa está formada por una gran variedad de principios activos, que reciben el nombre de cannabinoides. Existen 3 tipos diferentes de cannabinoides: los endocannabinoides, los fitocannabinoides y los cannabinoides sintéticos. Este estudio se centra en el desarrollo del CBD, puesto que es un producto que produce mínimos o nulos efectos psicoactivos y carece de toxicidad frente a los animales.La gran mayoría de los animales presentan un sistema endocannabinoide, formado por agonistas endóge-nos y sus receptores. Asimismo, fisiológicamente interviene en la regulación de la analgesia, el aprendizaje, la actividad locomotora, la ansiedad, el apetito, la motilidad gastrointestinal, el control inmune y la función cardiovascular. El CBD actúa en multitud de receptores en el organismo produciendo una gran diversidad de acciones terapéuticas.La osteoartrosis es una enfermedad autodegenerativa articular, cuyo principal signo clínico es el dolor. Actual-mente, el manejo farmacológico de la OA puede no producir una correcta analgesia y generar efectos indeseables. En este estudio se propuso como principal objetivo determinar si el CBD podría ser una alternativa en el tratamiento de la OA o bien utilizarse conjunto a un tratamiento multimodal. Para ello, se escogieron 5 artículos diferentes. Los resultados de los estudios demostraron que el CBD disminuía notablemente la sensación de dolor y me-joraba la calidad de vida. No se observaron signos clínicos secundarios a su administración, a excepción de un aumento de la fosfatasa alcalina. Existiendo la posibilidad de que el uso del CBD pudiera ocasionar daño hepático. Las conclusiones que se pueden sacar de este estudio es que el CBD es un producto que presenta un gran potencial terapéutico, una dosis efectiva mínima y mínimos efectos adversos. Demostrando ser un fármaco muy completo, que necesita más estudios para poder utilizarse de manera más amplia y sin riesgos
- PublicationOpen AccessPharmacokinetic/pharmacodynamic modeling in plasma and milk and Mote Carlo simulations of marbofloxacin against Staphylococcu aureus and Mycoplasma agalactie in lactating sheep(Elsevier, American Dairy Science Association, 2025-03-24) Serrano-Rodríguez, J. M.; Fernández-Varón, E.; Muñoz-Rascón, P.; Morón, R.; Díaz-Villamarín, X.; Fé Rodríguez, David Christian de la; Cárceles-García, C.; Cárceles Rodríguez, Carlos; Farmacología; Facultad de VeterinariaIn livestock ruminants such as sheep, different infectious diseases such as mastitis or contagious agalactia are originated from pathogens as Staphylococcus aureus and Mycoplasma agalactiae. Fluoroquinolones are authorized in dairy animals, including their extralabel use, as an alternative when other treatment failed in the European Union (EU), however, in the United States, are prohibited from extralabel drug use in food-producing animals. Marbofloxacin, a well-known fluoroquinolone is commonly used in dairy cattle in the EU at 10 mg/kg. However, their off-label use in sheep also has been described. Nevertheless, the dose extrapolations from dairy cows should include pharmacokinetic (PK) studies because of interspecies differences and the potential risks of antimicrobial resistance or toxicity. In this regard, the aims of this research were to (1) describe the i.v. and i.m. PK analysis of marbofloxacin in plasma and milk of lactating sheep at 10 mg/kg, (2) determine the MIC and calculate the tentative epidemiological cutoff values (TECOFF) for Mycoplasma agalactiae and Staphylococcus aureus wild-type isolates from sheep, and (3) conduct a pharmacokinetic and pharmacodynamic (PK/PD) analysis with the Monte Carlo simulation to obtain the probability of target attainment for different MIC values, known as the PK/PD cutoff values. The results of this study could help to establish the efficacy of a 10 mg/kg dosage regimen of marbofloxacin in lactating sheep. Plasma and milk concentrations were described with a nonlinear mixed effects model. The intramuscular biobioavailability was 88%, and the volume of distribution was 1.31 L/kg with a clearance value of 0.38 L/h/kg. Halflives after i.v. and i.m. dosing were 6.53 and 7.09 h in plasma, and 6.62 and 6.65 h in milk, respectively. High concentrations were determined in milk with area under the curve (AUC) milk/plasma ratios close to 1.28. The MIC values for Staphylococcus aureus and Mycoplasma agalactiae were obtained, and TECOFF values of 1.0 and 2.0 μg/mL, respectively, were determined. The Monte Carlo simulations predicted that the dosage regimen of 10 mg/kg per 24 h in lactating sheep can be adequate for intermediate and high MIC values of 0.5 and 1.0 μg/mL, respectively, and could be useful for populations with a target AUC/MIC ratio ≤48 for Staphylococcus aureus, but not for Mycoplasma agalactiae. Results derived for this study could be taken as previous tentative points for further studies of marbofloxacin in lactating and nonlactating sheep in a clinical context.
- PublicationRestrictedPharmacokinetics and sedative effects of alfaxalone with or without dexmedetomidine in rabbits(Elsevier, 2020-04) Marín Carrillo, Pedro; Belda Mellado, Eliseo; Laredo Álvarez, Francisco Ginés; Torres, Crhystian A.; Hernandis Belenguer, Verónica; Escudero Pastor, Elisa; FarmacologíaThis study aimed to investigate the specific pharmacokinetic profile and effects of alfaxalone after intravenous (IV) and intramuscular (IM) administration to rabbits and evaluate the potential interaction with dexmedetomidine. The study design was a blinded, randomized crossover with a washout period of 2 weeks. Five New Zealand white rabbits were used. Each animal received single IV and IM injections of alfaxalone at a single dose of 5 mg/kg, and single IV and IM injections of alfaxalone (5 mg/kg) combined with dexmedetomidine (100 μg/kg) administered intramuscularly. Blood samples were collected at predetermined times and analysed by high-performance liquid chromatography. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation/anaesthesia scores were evaluated by a modified numerical rating scale. At pre-determined time points heart and respiratory rates were measured. Times to sternal recumbency and standing position during the recovery were recorded. Concentrations of alfaxalone alone were very similar (slighty smaller) to concentrations when alfaxalone was combined with dexmedetomidine, after both routes of administration. Dexmedetomidine enhanced and increase the duration of the sedative effects of alfaxalone. In conclusion, alfaxalone administered in rabbits provides rapid and smooth onset of sedation. After IV and IM injections of alfaxalone combined with dexmedetomidine, a longer MRT and a deeper and extended sedation have been obtained compared to alfaxalone alone. Consequently, alfaxalone alone or in combination with dexmedetomidine could be useful to achieve respectively moderate to deep sedation in rabbits.
- PublicationOpen AccessPharmacokinetics of Doxycycline in Plasma and Milk after Intravenous and Intramuscular Administration in Dairy Goats(MDPI, 2024) Martínez, José; Escudero, Elisa; Badillo, Elena; Yuste Pérez, María Teresa; Galecio, Juan Sebastián; Marin, Pedro; FarmacologíaDoxycycline is a second-generation tetracycline, marketed in different species for treating infections caused by susceptible bacteria. Little information is available on the pharmacokinetics of doxycycline in lactating goats. The objective of this study was to establish the disposition kinetics of doxycycline after parenteral administration (intravenous and intramuscular) in dairy goats and its elimination in milk. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for intravenous administration and 20 mg/kg for extravascular administrations. Noncompartmental pharmacokinetic methods were used to calculate plasma concentration–time data. The Vz value suggests a moderate distribution of this antibiotic in goats, with a value of 0.85 L/kg. A low bioavailability (F = 45.60%) of doxycycline following an intramuscular injection was observed, with all animals exhibiting signs of lameness. Doxycycline rapidly crossed the blood–milk barrier, but exposure to the antimicrobial and the concentrations reached in milk were lower than those obtained in plasma. Although PK/PD ratios may be low with the pharmacokinetic data obtained with this formulation of doxycycline, at this dose and route of administration, doxycycline after IM administration could be useful for infections by moderate or highly susceptible bacteria in the mammary gland of goats. However, it may be necessary to test different doses of doxycycline or other routes of administration to achieve better surrogate markers and to establish repeated dosing regimens and clinical efficacy.
- PublicationOpen AccessPharmacokinetics of Metformin in Combination With Sitagliptin in Adult Horses After Enteral Administration(Elsevier, 2019-01) Cárceles-Rodríguez, Carlos M.; Fernández-Varón, Emilio; Martín-Gimenez, Tamara; Aguirre, Carla; Arion, Alexandra; Rodríguez, María J.; Ayala de la Peña, Ignacio; Medicina y Cirugía AnimalInsulin dysregulation (ID) is a common metabolic disorder in horses. Recently, incretin hormone release has been suggested to be involved in ID in horses. In human medicine, metformin and sitagliptin are commonly used in combination for metabolic syndrome. This combination could be useful in treating ID in horses. However, no pharmacokinetics data have been reported in this species. The objective of the present study was to establish the plasma concentration–time profile and to derive pharmacokinetics data for a combination of metformin and sitagliptin in horses after enteral administration. Six healthy adult Purebred Spanish horses were used. A metformin (15 mg/kg) plus sitagliptin (1.5 mg/kg) preparation was administered by intragastric route (IG) as an enteral solution. Blood samples were collected from 0 to 48 hours after IG drug administration. Plasma concentrations of metformin and sitagliptin were measured using HPLC methods. The t½λz for metformin was 2.9 hours and for sitagliptin 21 hours. The Cmax was 442 ± 84 mg/L within 0.9 hours for metformin and 94 ± 14 mg/L within 1.3 hours for sitagliptin. No adverse effects were observed, and the combination of metformin and sitagliptin was well tolerated. Therefore, these results suggest that metformin plus sitagliptin might be a combination to consider in horses with ID. Additional studies are needed to establish the effectiveness and tolerance in equids affected by endocrine disorders.
- PublicationRestrictedPharmacokinetics of tildipirosin in horses after intravenous and intramuscular administration and its potential muscle damage(Elsevier, 2022-07-23) Galecio Naranjo, Juan Sebastian; Escudero Pastor, Elisa; Badillo Puerta, Elena; Marín Carrillo, Pedro; FarmacologíaTildipirosin is a novel semisynthetic macrolide antibiotic exclusively used in veterinary practice to treat respiratory infections. There are no pharmacokinetic or safety information available regarding the use of tildipirosin after intramuscular administration in horses. Thus, the objective of this work was to determine the disposition kinetics of tildipirosin after intravenous (IV) and intramuscular (IM) administration in horses and its potential muscle damage and cardiotoxicity. Six mature, Spanish-breed horses were used in a crossover study with a washout period of 30 days. Tildipirosin (18%) was administered at single doses by IV (2 mg/kg) and IM (4 mg/kg) routes. Tildipirosin plasma concentrations were determined by HPLC assay with ultraviolet detection. Muscle damage and inflammation were assessed by creatine kinase (CK) and haptoglobin (Hp), respectively. Creatine kinase myocardial band (CK-MB) and troponin (Tn) were used to evaluate cardiotoxicity. Tildipirosin in horses reached peak concentrations (Cmax = 1.13 μg/mL) at 0.60 h (tmax) after IM administration with an absolute bioavailability of 109.2%. Steady-state volume of distribution and clearance were 3.31 ± 0.57 L/kg and 0.22 ± 0.02 L/h/kg, respectively. Tildipirosin did not cause cardiotoxicity since CK-MB and Tn basal levels were not significantly different from those obtained after several days post-administration. Mild local reactions were observed after IM administration. This local inflammation was associated with mild myolysis (CK 239–837 UI/L), which was detectable for 48 h. In brief, tildipirosin could help to treat respiratory infections in horses because it showed extensive distribution, high bioavailability and did not provoke general adverse reactions.