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    Effect of ketoprofen on intravenous pharmacokinetics of ganciclovir in chukar partridges (Alectoris chukar)
    (Wiley, 2022) Corum, Orhan; Uney, Kamil; Corum, Duygu Durna; Atik, Orkun; Coskun, Devran; Zhunushova, Aidai; Elmas, Muammer
    The aim of the study was to determine the effect of ketoprofen (2 mg/kg) on the intravenous pharmacokinetics of ganciclovir (10 mg/kg) in chukar partridges (Alectoris chukar). Eight clinically healthy partridges were used in the study. The study was performed in two periods using a cross-over design following a 15-day drug washout period. Plasma concentrations of ganciclovir were determined using the high-pressure liquid chromatography-ultraviolet detector and analyzed by non-compartmental analysis. The elimination half-life (t(1/2 lambda z)), area under the concentration-time curve (AUC(0-infinity)), total body clearance, and volume of distribution at steady state of ganciclovir were 1.63 h, 33.22 h*mu g/ml, 0.30 L/h/kg, and 0.53 L/kg, respectively. Ketoprofen administration increased the t(1/2 lambda z) and AUC(0-infinity) of ganciclovir by 78% and 108%, respectively, and while decreased Cl-T by 53%. The increased plasma concentration and prolonged elimination half-life of ganciclovir caused by ketoprofen may result in the prolonged duration of action and therapeutic effect of ganciclovir. However, the concomitant use requires determination of the pharmacokinetics of ketoprofen and the safety of both drugs.
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    Effects of Temperature on the Pharmacokinetics, Tissue Residues, and Withdrawal Times of Doxycycline in Rainbow Trout (Oncorhynchus mykiss) following Oral Administration
    (Mdpi, 2023) Corum, Orhan; Uney, Kamil; Terzi, Ertugrul; Corum, Duygu Durna; Coskun, Devran; Altan, Feray; Elmas, Muammer
    Simple Summary Doxycycline, an approved aquacultural antibiotic, is extensively used in the treatment of bacterial diseases in fish. Since fish are poikilothermic organisms, their body temperature and metabolic rate are primarily influenced by the temperature of the water. Therefore, temperature may be affected by pharmacokinetic behavior and withdrawal times of drugs. The current study was undertaken to look at the differences in pharmacokinetics, tissue residues, and withdrawal times of doxycycline following oral administration in rainbow trout reared at 10 and 17 & DEG;C. The increment of water temperature from 10 to 17 & DEG;C decreased the elimination half-life, the body clearance, and the distribution volume of doxycycline and increased plasma concentrations. The withdrawal times for plasma and tissues decreased with the temperature increase. The results contributed to the determination of an optimal dosing regimen and the safe consumption of edible tissues in rainbow trout that were administered doxycycline and reared at different temperatures. The purpose of this study was to compare the pharmacokinetics, tissue residues, and withdrawal times of doxycycline after oral administration in rainbow trout reared at 10 and 17 & DEG;C. Fish received a 20 mg/kg oral dose of doxycycline after a single or 5-day administration. Six rainbow trout were used at each sampling time point for plasma and tissue samples, including liver, kidney, and muscle and skin. The doxycycline concentration in the samples was determined using high-performance liquid chromatography with ultraviolet detector. The pharmacokinetic data were evaluated by non-compartmental kinetic analysis. The WT 1.4 software program was used to estimate the withdrawal times. The increase of temperature from 10 to 17 & DEG;C shortened the elimination half-life from 41.72 to 28.87 h, increased the area under the concentration-time curve from 173.23 to 240.96 h * & mu;g/mL, and increased the peak plasma concentration from 3.48 to 5.50 & mu;g/mL. At 10 and 17 & DEG;C, the doxycycline concentration was obtained in liver > kidney > plasma > muscle and skin. According to the MRL values stated for muscle and skin in Europe and China (100 & mu;g/kg) and in Japan (50 & mu;g/kg), the withdrawal times of doxycycline at 10 and 17 & DEG;C were 35 and 31 days, respectively, for Europe and China and 43 and 35 days, respectively, for Japan. Since temperature significantly affected pharmacokinetic behavior and withdrawal times of doxycycline in rainbow trout, temperature-dependent dosing regimens and withdrawal times of doxycycline might be necessary.
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    Pharmacokinetics and bioavailability of carprofen in sheep
    (Wiley, 2022) Coskun, Devran; Corum, Orhan; Durna Corum, Duygu; Uney, Kamil; Elmas, Muammer
    The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations of a parenteral formulation at a dose of 4 mg/kg. A total of eight sheep were used for the investigation. The study comprised four periods, according to a crossover design with a 21-day washout period between treatments. Plasma concentrations of carprofen were measured using HPLC-UV. Pharmacokinetic parameters were estimated by non-compartmental model analysis. Following IV administration, t(1/2 lambda z), Cl-T, and V-dss were 43.36 h, 1.98 ml/h/kg, and 121.36 ml/kg, respectively. The C-max(obs) was 26.57 mg/ml for the IM, 23.76 mg/ml for the SC, and 15.90 mg/ml for the PO. The bioavailability following IM, SC, and PO administrations was 75.47%, 82.00%, and 62.51%, respectively. Plasma creatine kinase activity increased significantly at 3, 6, and 12 h following IM administration of carprofen. Despite differences in plasma concentrations and bioavailability among administration routes, carprofen at 4 mg/kg dose may provide the plasma concentration (>1.5 mu g/ml) needed for analgesic effect during 144 h in all routes. However, because of the slow absorption rate after SC and PO routes, the IV route may be preferred primarily for the rapid onset in the analgesic and anti-inflammatory effect of carprofen in sheep. Despite the favorable kinetics, the muscle damage caused by IM injection limits use of carprofen via IM route.
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    Pharmacokinetics and Plasma Protein Binding of Flunixin in Rainbow Trout (Oncorhynchus mykiss)
    (Wiley, 2024) Uney, Kamil; Corum, Orhan; Corum, Duygu Durna; Coskun, Devran; Sakin, Fatih; Elmas, Muammer
    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 degrees 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 (t(1/2 lambda z)) for flunixin was 8.37 h for IV, 8.68 h for IM, and 8.76 h for oral. The t(1/2 lambda z) 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 mu g/mL at 4 h for oral administration and 13.98 +/- 0.86 mu g/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.
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    Plasma and Milk Pharmacokinetics and Estimated Milk Withdrawal Time of Tolfenamic Acid in Lactating Sheep
    (Wiley, 2024) Corum, Orhan; Uney, Kamil; Coskun, Devran; Durna Corum, Duygu; Cetin, Gul; Elmas, Muammer
    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 (AUC(0-infinity), from 9.46 to 30.11 h mu g/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 (C-max) and AUC(0-infinity) values in milk were 0.26 mu g/mL and 0.28 h mu g/mL, respectively, for 2 mg/kg, and 0.43 mu g/mL and 0.55 h mu g/mL, respectively, for 4 mg/kg. Although the dose-normalized C-max of milk decreased depending on the dose, no difference was observed in dose-normalized AUC(0-infinity). The AUC(0-infinity milk)/AUC(0-infinity 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.