Farmakokinetika enrofloksacina u srodnih i nesrodnih kunića.

The pharmacokinetics of enrofloxacin (ENR) were investigated after intravenous (i/v) administration in inbred (n = 10) and outbred (n = 10) healthy rabbits. After i/v ENR injection the elimination half-life (t1/2β), total body clearance (ClB) and the area under the concentration vs. time curve (AUC) in inbred rabbits were 1.51 h, 28.35 ± 1.51 ml/kg/min and 3.01 ± 0.16 μg.h/ml, respectively. The value of t1/2β in outbred rabbits was 2.12 h. The value of ClB (21.47 ± 1.16 ml/kg/min) was significantly lower in outbred rabbits. There were no differences in pharmacokinetic parameters between male outbred and inbred rabbits, and only the value of ClB in female outbred rabbits was significantly lower in comparison to inbred animals. The phenotypic diversity, a manifestation of the complex interaction among the genotype and the environmental factors (the ENR treatment), was clearly less manifested in the inbred group than in outbreds.Farmakokinetika enrofl oksacina istraživana je nakon intravenske (i/v) primjene u zdravih srodnih (n = 10) i nesrodnih (n = 10) kunića. U srodnih kunića poluvrijeme izlučivanja lijeka iz plazme (t1/2β) iznosilo je 1,51 sat, ukupni klirens lijeka iz organizma (ClB) 28,35 ± 1,51 mL/kg/min, a područje pod koncentracijom u odnosu na vremensku krivulju (AUC) 3,01 ± 0,16 μg/h/mL. Vrijednost t1/2β u nesrodnih kunića bila je 2,12 h. Vrijednost ClB (21,47 ± 1,6 mL/kg/min) bila je značajno niža u nesrodnih kunića. Nisu ustanovljene razlike u farmakokinetici između srodnih i nesrodnih mužjaka. Jedino je ClB u nesrodnih ženki bio značajno niži u odnosu na vrijednost u srodnih ženki. Fenotipska raznolikost, pokazatelj zamršenog međudjelovanja između genotipa i okolišnih čimbenika (davanje enrofloksacina), slabije se očitovala u srodnih nego u nesrodnih kunića

Farmakokinetika oleandomicina primijenjenog samostalno i nakon peroralne primjene askorbinske kiseline trima vrstama ptica.

The influence of ascorbic acid administration via drinking water at a dose of 15 mg/l over a period of 7 days on the pharmacokinetics of oleandomycin in chickens, musk ducks and Japanese quails was investigated. After ascorbic acid oleandomycin elimination, half-life was longer. Oleandomycin bioavailability in chickens and quails after per os application was increased with ascorbic acid. Interspecies differences in oleandomycin body disposition were observed. Lower elimination rate constants were obtained in the musk ducks in comparison with two other species. The volume of distribution (Vss) was larger in quails. In conclusion, ascorbic acid did not change oleandomycin disposition significantly in the treated birds.Istražen je učinak askorbinske kiseline primijenjene u vodi za piće u dozi 15 mg/l u tijeku 7 dana na farmakokinetiku oleandomicina u kokoši, mošusnih pataka i japanskih prepelica. Poluvrijeme eliminacije oleandomicina bilo je duže u ptica tretiranih askorbinskom kiselinom, a bioraspoloživost mu je porasla u kokoši i prepelica nakon peroralne primjene. Opažene su vrsne razlike u raspodjeli oleandomicina. U usporedbi s kokošima i japanskim prepelicama, u mošusnih pataka zabilježene su niže vrijednosti konstanti opsega eliminacije. Volumen raspodjele (Vss) bio je veći u prepelica. Zaključuje se da askorbinska kiselina ne utječe značajno na raspodjelu oleandomicina u tretiranih ptica

Raspodjela sulfaklorpirazina u pilića invadiranih vrstom Eimeria tenella.

The control of coccidiosis in chickens is undertaken mainly by administration of anticoccidial drugs. Sulfachloropyrazine-sodium is still used as an effective coccidiocidal compound to treat poultry with clinical signs of coccidiosis. However, its disposition after three days treatment in Eimeria tenella infected chickens has not been well studied. Pharmacokinetics of sulfachlorpyrazine-sodium was investigated in healthy chickens and chickens experimentally infected with E. tenella. Serum and tissue concentrations were determined by HPLC-PDA analysis. The values of absorption half-life (17.24 ± 3.50 h) and time for achievement of maximal serum concentrations Tmax (23.41 ± 3.78 h) of the sulfonamide were significantly higher in infected chickens. An accumulation index of 1.22 ± 0.13 was estimated and significantly higher serum concentrations were observed in E. tenella challenged animals. Significantly higher sulfachloropyrazine-sodium levels were found in the duodenum, caeca and the liver, which suggests that a longer withdrawn time could be expected in infected chickens after three days administration of the anticoccidial agent. The observed changes in sulfachloropyrazine disposition could be attributed to the alteration of the integrity of the intestines and decreased motility of the gastro-intestinal tract during the clinical coccidiosis.Kontrola kokcidioze u pilića pretežito se provodi primjenom protukokcidijskih lijekova (kokcidiostatika). Natrijev sulfaklorpirazin se još uvijek rabi kao učinkovit kokcidiocidni sastojak za liječenje peradi s kliničkim znakovima kokcidioze. Ipak, njegova raspodjela nakon tri dana liječenja nije dovoljno istražena u pilića zaraženih vrstom Eimeria tenella. Farmakokinetika natrijeva sulfaklorpirazina u ovom je radu istražena u zdravih i pokusno invadiranih pilića parazitom E. tenella. Njegove koncentracije u serumu i tkivima bile su određivane metodom HPLC-PDA. Vrijednosti poluvremena apsorpcije (17,24 ± 3,50 h) i vremena za postizanje najvećih koncentracija u serumu Tmax (23,41 ± 3,78 h) bile su značajno veće u zaraženih pilića. Procijenjeni akumulacijski indeks bio je 1,22 ± 0,13, a značajno veće serumske koncentracije bile su ustanovljene u zaraženih životinja. Značajno veće razine sulfaklorpirazina bile su dokazane u dvanaesniku, slijepim crijevima i jetri što govori da se može očekivati duže vrijeme izlučivanja u zaraženih pilića nakon trodnevne primjene antikokcidijske tvari. Ustanovljene promjene u raspodjeli sulfaklorpirazina mogu se pripisati promjeni integriteta crijeva i smanjenom motilitetu želučano-crijevnog sustava kod kliničke kokcidioze

Use of quercetin in animal feed : effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken

Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.Peer reviewedFinal Published versio

Pharmacokinetic aspects of retinal drug delivery

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.Peer reviewe

Phenotypic and genetic variation in the response of chickens to Eimeria tenella induced coccidiosis

Background: Coccidiosis is a major contributor to losses in poultry production. With emerging constraints on the use of in-feed prophylactic anticoccidial drugs and the relatively high costs of effective vaccines, there are commercial incentives to breed chickens with greater resistance to this important production disease. To identify phenotypic biomarkers that are associated with the production impacts of coccidiosis, and to assess their covariance and heritability, 942 Cobb500 commercial broilers were subjected to a defined challenge with Eimeria tenella (Houghton). Three traits were measured: weight gain (WG) during the period of infection, caecal lesion score (CLS) post mortem, and the level of a serum biomarker of intestinal inflammation, i.e. circulating interleukin 10 (IL-10), measured at the height of the infection.Results: Phenotypic analysis of the challenged chicken cohort revealed a significant positive correlation between CLS and IL-10, with significant negative correlations of both these traits with WG. Eigenanalysis of phenotypic covariances between measured traits revealed three distinct eigenvectors. Trait weightings of the first eigenvector, (EV1, eigenvalue = 59%), were biologically interpreted as representing a response of birds that were susceptible to infection, with low WG, high CLS and high IL-10. Similarly, the second eigenvector represented infection resilience/resistance (EV2, 22%; high WG, low CLS and high IL-10), and the third eigenvector tolerance (EV3, 19%; high WG, high CLS and low IL-10), respectively. Genome-wide association studies (GWAS) identified two SNPs that were associated with WG at the suggestive level.Conclusions: Eigenanalysis separated the phenotypic impact of a defined challenge with E. tenella on WG, caecal inflammation/pathology, and production of IL-10 into three major eigenvectors, indicating that the susceptibility-resistance axis is not a single continuous quantitative trait. The SNPs identified by the GWAS for body weight were located in close proximity to two genes that are involved in innate immunity (FAM96B and RRAD)

PK-PD Modeling of Fluoroquinolones and ABC Transporters in Poultry

In the first part of this thesis advance pharmacokinetic models, based on an integration of pharmacokinetic and pharmacodynamic data for selected fluotoquinolones, are presented. The comparative investigations with danofloxacin mesylate and marbofloxacin indicated that with both fluoroquinolones a concentration-dependent killing of E. coli O78/K80 can be achieved in vitro, but that in vivo danofloxacin mesylate shows lower values for the AUC24/MIC ratio as compared to marbofloxacin. This PK-PD approach allows a direct comparison of different antibiotics and can serve as guidance in the design of dosage regimens for forthcoming clinical trails. In the interpretation of these data it should be considered, that the calculation of the optimal dose in this model is based on drug plasma levels, and not on tissue concentrations. The latter determine, however, the concentration at the site of infection in most cases. Moreover, physiological changes during an infection are incompletely reflected in these commonly used models. As the first step towards a refinement of these kinetic analyses, a pilot study with implanted tissue chambers was conducted. This study showed that subcutaneous tissue cages could be used in poultry as well. Implanted cages could be infected with test organisms that produce a local inflammatory reaction, without affecting the wellbeing of the animal significantly. This model offers broad possibilities to study the kinetics and typical pharmacodynamic characteristics of antimicrobials and other pharmaceuticals under the conditions of an inflammatory reaction in the living animal. To refine the limited information than can be obtained from the plasma levels of a drug, the factors involved in absorption and tissue distribution of a given drug or toxin should be known. Transport proteins, particularly by the so-called ABC proteins, which are able to expel various substances out of the cell, determine often the tissue distribution. The strategic localization of these proteins at mucosal surfaces such as the intestinal mucosa, or the pulmonary alveolar surfaces, in excretory organs, such as liver and kidneys, as well as at tissue barriers (such as the blood brain barrier) indicate the eminent role in absorption, distribution and excretion of drugs and toxins. At present, the knowledge about their tissue distribution and functions in poultry is very limited. Hence the expression of MDR1, MRP2 and BCRP, the three major transporters involved in drug transport across biological membranes in mammals, were investigated by quantitative PCR in chickens and in turkeys. The result was an expression map that served all forthcoming experiments. It could be shown that the level of expression and functional activity could be modulated by fluoroquinolones, although the fluoroquinolones that had been used for the kinetic studies did not significantly alter the activity of for example P-gp. Moreover, treatment of animals, experimentally infected with E. coli, with either fluoroquinolone showed that bacterial cure is accompanied by a rapid restoration of physiological P-gp expression (without significant effect on MRP2 expression). This restoration increases the functionality of the intestinal barrier as well as the function of other tissue barriers and is an essential parameter in the prediction of the therapeutic outcome of antibiotics