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Tugba Melike Parlak^orcid.org/0000-0003-3277-0336 1. Introduction Ivermectin is a semisynthetic derivative of avermectin B1 produced by Streptomyces avermitilis. This drug, which is widely used in veterinary medicine to combat ecto- and [...], This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8-10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A. Key words: drug disposition, ivermectin, vitamin A, vitamin E, mice

The aim of this study was to compare the pharmacokinetics of marbofloxacin after intravenous (IV) administration of a single dose of 10 mg/kg to calves of different ages. The study was carried on 1‐ (n = 6), 2‐ (n = 6), and 4‐month‐old (n = 6) Montofon calves. Plasma concentrations of marbofloxacin were measured using HPLC, and pharmacokinetic data were calculated by non‐compartmental analysis. The elimination half‐life (t1/2ʎz), volume of distribution at steady state (Vdss), total clearance (ClT), and area under the concentration‐versus time curve (AUC0–∞) values of marbofloxacin in 1‐month‐old calves were 10.62 h, 1.03 L/kg, 0.08 L/h/kg, and 127.90 h*μg/mL, respectively. While the t1/2ʎz (from 10.62 to 3.36 h) and AUC0–∞ (from 127.90 to 47.35 h*μg/mL) decreased in parallel with the age of the calves, ClT (from 0.08 to 0.21 L/h/kg) increased. The Vdss of marbofloxacin was higher in 1‐ and 2‐month‐old calves compared to 4‐month‐old calves. After IV administration of marbofloxacin at a dose of 10 mg/kg, an ƒAUC0–24/MIC90 ratio of ≥ 125 was obtained for bacteria with MIC90 values of ≤ 0.60, ≤ 0.39 and ≤ 0.27 μg/mL in 1‐, 2‐, and 4‐month‐old calves, respectively. These results show that the antibacterial effect of marbofloxacin, which has concentration‐dependent activity, decreases due to age‐related pharmacokinetic changes and that the 10 mg/kg dose should be reviewed according to the MIC90 value of the bacteria. [ABSTRACT FROM AUTHOR]

Simple Summary: Changes in body size in fish can alter the pharmacokinetics of drugs, thereby affecting their therapeutic efficacy. Fish are among the animals that exhibit the greatest variability in body size during their life cycle. Despite being exposed to bacterial infections at all stages of life, the dosage regimens of antibacterial drugs have not been adjusted for age/body mass changes. The plasma and tissue pharmacokinetics of danofloxacin differed according to rainbow trout size. Pharmacokinetic/pharmacodynamic findings suggest that treatment efficacy is positively correlated with body size. However, in natural infections caused by susceptible bacteria, pharmacokinetic/pharmacodynamic studies in different fish sizes are needed to define optimal dosing regimens. Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t1/2ʎz), volume of distribution (Vdarea/F), total clearance (CL/F), peak concentration (Cmax), and area under the plasma concentration–time curve (AUC0–last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t1/2ʎz, AUC0–last and Cmax increased concomitantly with trout growth, whereas CL/F and Vdarea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. Cmax and AUC0–last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the plasma and milk pharmacokinetics, as well as the withdrawal time (WT) from milk of tolfenamic acid (2 and 4 mg/kg) following intravenous (IV) administration to eight healthy lactating Akkaraman sheep. Methods: The trial was conducted in two periods in accordance with a crossover pharmacokinetic design. The concentrations of tolfenamic acid in the plasma and milk were determined using high‐pressure liquid chromatography and evaluated using non‐compartmental analysis. The WT of tolfenamic acid in milk was calculated using the WT 1.4 software. Results: Compared to the 2 mg/kg dose, plasma volume of distribution at steady state (from 0.43 to 0.50 L/kg), terminal elimination half‐life (from 2.41 to 4.14 h) and dose‐normalized area under the plasma concentration–time curve (AUC0−∞, from 9.46 to 30.11 h µg/mL) increased, whereas total body clearance (from 0.21 to 0.13 L/h/kg) decreased at the 4 mg/kg dose. The peak milk concentration (Cmax) and AUC0−∞ values in milk were 0.26 µg/mL and 0.28 h µg/mL, respectively, for 2 mg/kg, and 0.43 µg/mL and 0.55 h µg/mL, respectively, for 4 mg/kg. Although the dose‐normalized Cmax of milk decreased depending on the dose, no difference was observed in dose‐normalized AUC0−∞. The AUC0−∞ milk/AUC0−∞ plasma ratio was 0.03 for 2 mg/kg and 0.02 for 4 mg/kg. The WT values calculated for milk at dosages of 2 and 4 mg/kg were 3 and 4 h, respectively. Conclusions: A decrease in plasma elimination and an increase in plasma concentration of tolfenamic acid were observed depending on the dose. Tolfenamic acid lowly passed into sheep's milk at 2 and 4 mg/kg doses. This study may provide valuable information for clinicians' decision‐making processes. [ABSTRACT FROM AUTHOR]

ABSTRACT Flunixin's pharmacokinetics, bioavailability, and plasma protein binding were examined in rainbow trout. The experiment involved 252 rainbow trout (Oncorhynchus mykiss) maintained at 12 ± 0.6°C. Flunixin was administered to rainbow trout via intravascular (IV), intramuscular (IM), and oral routes at a dosage of 2.2 mg/kg. Plasma samples were collected at times 0 (control), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, and 96 h. High‐pressure liquid chromatography‐ultraviolet was employed to quantify flunixin concentrations. The elimination half‐life (t1/2ʎz) for flunixin was 8.37 h for IV, 8.68 h for IM, and 8.76 h for oral. The t1/2ʎz was similar between administration groups. The volume of distribution at a steady state and total body clearance were 55.81 mL/kg and 6.83 mL/h/kg, respectively, after IV administration. The mean peak plasma concentration was 6.24 ± 0.41 μg/mL at 4 h for oral administration and 13.98 ± 0.86 μg/mL at 2 h for IM administration. The in vitro protein binding ratio of flunixin in rainbow trout plasma was 96.34 ± 2.29%. The bioavailability of flunixin after oral (25.74%) administration was lower than that after IM (66.70%) administration. Thus, developing an oral pharmaceutical formulation that can be administered with feed and has high bioavailability could enhance the therapeutic effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non‐steroidal anti‐inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. Objectives: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. Methods: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography–ultraviolet (UV) and pharmacokinetic parameters were assessed using non‐compartmental analysis. Results: The elimination half‐life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. Conclusions: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout. [ABSTRACT FROM AUTHOR]

Objective: Doxycycline (DO) has been used in fish for a long time, but there are some factors that have not yet been clarified regarding its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, the aim of this study was to investigate the PK and PK/PD targets of DO after 20 mg/kg intravascular (IV), intramuscular (IM) and oral (OR) gavage administration in rainbow trout (Oncorhynchus mykiss). Methods: Plasma samples were collected at specific time points and subsequently analysed by HPLC‐ultraviolet. The PK/PD indices were calculated based on the MIC90 (Aeromonas hydrophila and Aeromonas sobria) values obtained for the respective bacteria and the PK parameters obtained for DO following both IM and OR administration. Results: After IV administration, the elimination half‐life (t1/2ʎz), area under the concentration vs. time curve (AUC), apparent volume of distribution at steady‐state and total body clearance of DO were 34.81 h, 723.82 h µg/mL, 1.24 L/kg and 0.03 L/kg/h, respectively. The t1/2λz of the DO was found to be 37.39 and 39.78 h after IM, and OR administration, respectively. The bioavailability was calculated 57.02% and 32.29%, respectively, after IM and OR administration. The MIC90 of DO against A. hydrophila and A. sobria was 4 µg/mL. The PK/PD integration showed that DO (20 mg/kg dose) for A. hydrophila and A. sobria with MIC90 ≤4 µg/mL achieved target AUC/MIC value after IM administration. Conclusions: These results suggest that when rainbow trout was treated with 20 mg/kg IV and IM administered DO, therapeutically effective concentrations were reached in the control of infections caused by A. hydrophila and A. sobria. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine the pharmacokinetic change after intravenous administration of meloxicam at doses of 0.5, 1 and 2 mg/kg to sheep. The study was carried out on six Akkaraman sheep. Meloxicam was administered intravenously to each sheep at 0.5, 1, and 2 mg/kg doses in a longitudinal pharmacokinetic design with a 15‐day washout period. Plasma concentrations of meloxicam were determined using the high performance liquid chromatography‐ultraviolet, and pharmacokinetic parameters were evaluated by non‐compartmental analysis. Meloxicam was detected up to 48 h in the 0.5 mg/kg dose and up to 96 h in the 1 and 2 mg/kg doses. As the dose increased from 0.5 to 2 mg/kg, terminal elimination half‐life, and dose normalized area under the concentration versus time curve increased and total clearance decreased. Compared to the 1 mg/kg dose, it was determined that Vdss decreased and C0.083h increased in the 2 mg/kg dose. Meloxicam provided the therapeutic concentration of >0.39 μg/mL reported in other species for 12, 48 and 96 h at 0.5, 1 and 2 mg/kg doses, respectively. These results show that meloxicam exhibits non‐linear pharmacokinetics and will achieve unpredictable plasma concentrations when administered IV for a rapid effect at dose of ≥1 mg/kg in sheep. [ABSTRACT FROM AUTHOR]

Letrozole is a non‐steroidal, third‐generation aromatase inhibitor used in humans. Although letrozole is not approved for use in animals, it is used off‐label in cases of synchronization and infertility. The aim of this study was to determine the pharmacokinetics of letrozole after a single intravenous administration at three different doses in ewes during the breeding season and its effect on gonadotropins (luteinizing hormone (LH) and follicle‐stimulating hormone (FSH)) at the beginning of proestrus. The study was carried out on 24 healthy Merino ewes. Ewes were randomly divided into four groups (n = 6) as control, 0.5, 1, and 2 mg/kg. Plasma concentrations of letrozole were measured using HPLC‐UV and were analyzed by non‐compartmental analysis. LH and FSH concentrations were measured with a commercial ELISA kit. The terminal elimination half–life (t1/2ʎz) was significantly prolonged from 11.82 to 18.44 h in parallel with the dose increase. The dose‐normalized area under the concentration–time curve (AUC) increased, and total body clearance (ClT) decreased at the 1 and 2 mg/kg doses (0.05 L/h/kg) compared with the 0.5 mg/kg dose (0.08 L/h/kg). There were no differences in the volume of distribution at steady‐state and initial (C0.083h) plasma concentration values between dose groups. The decreased ClT, prolonged t1/2ʎz, and increased AUC at increasing doses showed the nonlinear kinetic behavior of letrozole. Letrozole significantly reduced LH concentration without affecting FSH concentration at all doses. As a result, letrozole has the potential to be used in synchronization methods and manipulation of the follicular waves due to its effect on LH secretion. [ABSTRACT FROM AUTHOR]

Introduction Type 2 diabetes has now become a serious worldwide public health problem (Selvaraju et al. 2012). Diabetes is characterized by reduced insulin secretion or defects in insulin activity resulting [...], In the present study, combined treatment with etanercept and anakinra were tested in the streptozotocin-induced diabetic rats. Forty male Wistar albino rats were divided into 5 groups: healthy control (HC), diabetic control (DC), diabetic + anakinra (DAT), diabetic + etanercept (DET), and diabetic + etanercept + anakinra (DEAT). HC and DC groups received subcutaneous (s.c.) injection with a saline solution, while DAT and DET groups received anakinra (10 mg/kg per day, s.c.) or etanercept (10 mg/kg, twice a week, s.c.), and DEAT rats received both anakinra and etanercept treatments for 21 days after diabetes has developed. Anakinra and etanercept treatments significantly increased insulin and homeostatic model assessment [beta]-cell function levels and decreased glucose levels compared to the DC group as single (DAT and DET) and combined treatments (DEAT). The thiobarbituric acid reactive substances level was significantly decreased in DAT group. The combine use of etanercept and anakinra can improve insulin and blood glucose in type 2 diabetic rats. The combined treatment of anakinra and etanercept together was more effective than single treatment and might have a potential new treatment strategy and to reduce the mortality and morbidity resulting from diabetes. Key words: etanercept, anakinra, type 2 diabetes mellitus, interleukin-1, tumor necrosis factor-alpha. Dans les presents travaux, nous avons etudie le traitement d&apos;association constitue de l&apos;etanercept avec l&apos;anakinra chez le rat atteint de diabete provoque par la streptozotocine. Nous avons reparti 40 rats Wistar albinos males dans 5 groupes : temoins en bonne sante (TS), temoins avec diabete (TD), diabete + anakinra (DA), diabete + etanercept (DE) et diabete + etanercept + anakinra (DEA). Les rats des groupes TS et TD ont recu des injections sous-cutanees (s.-c.) de solution saline, tandis que les rats des groupes DA et DE ont recu de l&apos;anakinra (10 mg/kg par jour, s.-c.) ou de l&apos;etanercept (10 mg/kg, deux fois par semaine, s.-c.), et les rats DEA ont recu de l&apos;anakinra avec de l&apos;etanercept pendant les 21 jours suivant l&apos;apparition du diabete. L&apos;administration d&apos;anakinra et d&apos;etanercept a entraine une augmentation marquee des taux d&apos;insuline et de fonctionnement des cellules [beta] selon le modele devaluation de l&apos;homeostasie, avec une diminution de la glycemie plus importantes dans les groupes de monotherapies (DA et DE) et de traitement d&apos;association (DEA) que dans le groupe DT. Nous avons observe une diminution marquee des taux de substances reagissant a l&apos;acide thiobarbiturique dans le groupe DA. L&apos;administration concomitante d&apos;etanercept et d&apos;anakinra peut permettre d&apos;obtenir des ameliorations en matiere d&apos;insuline et de glycemie chez les rats atteints de diabete de type 2. Le traitement d&apos;association par l&apos;anakinra avec l&apos;etanercept etait plus efficace que les monotherapies, ce qui pourrait en faire une nouvelle strategie de traitement et entrainer une diminution de la mortalite et de la morbidite comme consequences du diabete. [Traduit par la Redaction] Mots-cles: etanercept, anakinra, diabete sucre de type 2, interleukine 1, facteur de necrose tumorale alpha.

Caffeine (CF) is a metabolic probe drug used in the determination of the hepatic drug‐oxidizing capacity. The aim of this study was to investigate temporal changes in the hepatic drug‐oxidizing capacity using plasma metabolite/CF ratios in non‐pregnant goats (n = 11) and pregnant goats (n = 23). CF (5 mg/kg, intravenous) was administered in six periods (Period 1–6) with 45 days between two periods. The plasma levels of CF and its metabolites, theophylline (TP), theobromine (TB) and paraxanthine (PX), were determined by HPLC‐UV. To evaluate hepatic drug‐oxidizing capacity in terms of enzymes that play a role in CF metabolism, the plasma metabolic ratios including TB/CF, PX/CF, TP/CF and TB + PX + TP/CF were determined at 10 h following CF administration. Plasma metabolite/CF ratios were similar between non‐pregnant and pregnant goats. However, plasma metabolite/CF ratios in Period 3 (45 days in pregnant goats) were significantly higher than those other periods in both pregnant and non‐pregnant goats. The effect of pregnancy may not be observed on drugs that are substrates of enzymes involved in CF metabolism in goats. [ABSTRACT FROM AUTHOR]

The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three‐period, crossover pharmacokinetic design and on six healthy Awassi sheep 1–3 years of age. The plasma concentrations of oxfendazole and its metabolites (fenbendazole and fenbendazole sulphone) and oxyclozanide were determined by high‐performance liquid chromatography using an ultraviolet detector. Compounds recovered in plasma when oxfendazole was administered alone or combined with oxyclozanide were oxfendazole, fenbendazole sulphone, and fenbendazole, respectively. When oxfendazole was administered alone and co‐administered with oxyclozanide, the AUCFBZ/AUCOFZ was 0.26 and 0.23, respectively, and the AUCFBZSO2/AUCOFZ was 0.35 and 0.32, respectively. The volume of distribution (Vz/F) of oxfendazole was large in both groups. Oxyclozanide did not change the plasma disposition of oxfendazole. When the oxyclozanide tablet formulation was administered alone, the elimination half‐life (21.35 h) and the Vz/F (940.17 ml/kg) were long and large, respectively. The area under the curve (AUC) and the maximum plasma concentration of oxyclozanide were significantly larger and higher, respectively, in the oxyclozanide plus oxfendazole group (1146.61 h × μg/ml and 29.80 μg/ml) compared with the oxyclozanide group (491.44 h × μg/ml and 14.24 μg/ml) while a significant decrease in apparent Vz/F (940.17 vs 379.14 ml/kg) and total clearance (30.52 vs 13.08 ml/h/kg) was detected. In conclusion, co‐administration with oxfendazole causing an increase in the plasma profile of oxyclozanide may increase the antiparasitic activity of oxyclozanide. [ABSTRACT FROM AUTHOR]