Pharmacokinetics and residues of a new oral amoxicillin formulation in piglets: a preliminary study

The pharmacokinetics of amoxicillin (Amx) were determined in pigs following intravenous (IV) administration of a single dose of 15 mg/kg and a single dose of 15 mg/kg of a new oral formulation (Amx-FP containing 10% amoxicillin). Residue studies were performed to determine residues in edible tissues of healthy pigs after chronic oral administration of Amx-FP at a daily dose of 15 mg/kg for five consecutive days. After IV administration, the plasma concentration was characteristic of a two-compartment open model. The main pharmacokinetic variables were: t(1/2lambda(n)), MRT=90.1 min, V(darea)=0.81 L/kg and Cl(b)=3.9 mL/kg/min. After single oral administration the main pharmacokinetic variables were: C(max)=758 mug/L, t(max)=347 min and Cl(b/f)=3.7 mL/kg/min for Amx-FP. The oral bioavailability (F) was calculated at 11% for Amx-FP. Based on maximum residue levels (MRL) for AMX in pigs established at 50 microg/kg for all tissues, the withdrawal times of AMX in muscle and skin plus fat were estimated (95% tolerance limit and 95% confidence) to fall below the MRL after a withdrawal period of seven days. Levels of AMX in the liver and kidneys were estimated to fall below the MRL after a withdrawal period of four days.     

Absorption, tissue distribution and excretion of flumequine and oxolinic acid in corkwing wrasse (Symphodus melops) following a single intraperitoneal injection or bath treatment

The pharmacokinetic properties of the antibacterial agents oxolinic acid and flumequine were studied in corkwing wrasse (Symphodus melops) after either intraperitoneal injection or bath treatment. Following intraperitoneal administration the peak plasma concentrations (Cmax) and the time to peak plasma concentrations (Tmax) were estimated to be 2.0 microg/mL and 12 h, respectively, for oxolinic acid and 2.6 microg/mL and 12 h, respectively, for flumequine. In muscle, Cmax and Tmax were estimated to 6.7 microg/g and 12 h, respectively, for oxolinic acid with corresponding values of 8.5 microg/g and 13 h, respectively, for flumequine. In liver, Cmax and Tmax were calculated to 7.0 microg/g and 12 h, respectively, for oxolinic and 12.2 microg/g and 11 h, respectively, for flumequine. Elimination half-lives (t1/2 beta) of 26, 24 and 29 h, respectively, for plasma, muscle and liver were calculated for flumequine. For oxolinic acid two distinct elimination phases were found and calculated to be 16 h (t1/2 beta) and 57 h (t1/2 gamma) in plasma, 15 and 59 h, respectively, in muscle and 20 and 72 h, respectively, in liver. Bath treatment using 150 mg/L of flumequine or 200 mg/L of oxolinic acid for 72 h resulted in flumequine concentrations of 1.0 microg/mL in plasma, 5.0 microg/g in muscle and 12.4 microg/g in liver. Corresponding values for oxolinic acid were 1.0 microg/g in plasma, 2.5 microg/g in muscle and 4.9 microg/g in liver.     

Pharmacokinetics of potassium bromide in adult horses

OBJECTIVE: To determine the pharmacokinetics of potassium bromide (KBr) in horses after a single and multiple oral doses. ANIMALS: Twelve adult Standardbred and Thoroughbred mares. PROCEDURE: Horses were randomly assigned into two treatment groups. In Part 1 of the study, horses were given a single oral dose of 120 mg/kg KBr. Part 2 of the study evaluated a loading dose of 120 mg/kg KBr daily by stomach tube for 5 days, followed by 40 mg/kg daily in feed for 7 days. Serum concentrations of bromide were determined by colorimetric spectrophotometry following drug administration to permit determination of concentration versus time curves from which pharmacokinetic parameters could be calculated. Treated horses were monitored twice daily by clinical examination. Serum concentrations of sodium, potassium and chloride ions and partial pressures of venous blood gases were determined. RESULTS: Maximum mean serum bromide concentration following a single dose of KBr (120 mg/kg) was 284 +/- 15 microg/mL and the mean elimination half-life was 75 +/- 14 h. Repeated administration of a loading dose of KBr (120 mg/kg once daily for 5 days) gave a maximum serum bromide concentration of 1098 +/- 105 microg/mL. The administration of lower, maintenance doses of KBr (40 mg/kg once daily) was associated with decreased serum bromide concentrations, which plateaued at approximately 700 microg/mL. Administration of KBr was associated with significant but transient changes in serum potassium and sodium concentrations, and possible changes in base excess and plasma bicarbonate concentrations. High serum concentrations of bromide were associated with an apparent increase in serum chloride concentrations, when measured on an ion specific electrode. CONCLUSIONS AND CLINICAL RELEVANCE: A loading dose of 120 mg/kg daily over 5 days and maintenance doses of approximately 90-100 mg/kg of KBr administered once daily are predicted to result in serum bromide concentrations consistent with therapeutic efficacy for the management of seizures in other species. The clinical efficacy of this agent as an anticonvulsant medication and/or calmative in horses warrants further investigation.     

Plasma/muscle ratios of sulfadimethoxine residues in channel catfish (Ictalurus punctatus)

Channel catfish ( n = 84) maintained at a water temperature of 27°C were used in a feeding study to determine the plasma to muscle concentration ratios of sulfadimethoxine (SDM) and 4-N-acetylsulfadimethoxine residues. Sulfadimethoxine medicated feed was provided free choice at 42 mg SDM/kg body weight once daily for 5 days and the plasma and muscle concentrations of SDM were determined at selected withdrawal times (6, 12, 24, 48, 72, and 96 hours) following the last dose. Considerable variation in total SDM tissue concentration among fish within a sampling period was observed. For fish ( n = 12) at six hours post-dose, total SDM concentrations ranged from 1.4–24.8 μg/mL and 0.6–12.6 μg/g, with mean total SDM concentrations of 9.1 μg/mL and 5.3 μg/g for plasma and muscle, respectively. However, a mean plasma:muscle concentration ratio of 1.8:1 ± 0.3:1 was obtained over all concentrations and sampling periods. The plasma:muscle 95% t distribution interval for individual fish was 1.2:1 to 2.4:1. A correlation coefficient of 0.967 was obtained for the relationship between plasma and muscle total SDM concentration among individual fish ( n = 25). Results of this study indicate that plasma total SDM concentration may be used to identify samples containing violative SDM muscle residue. No fish contained total SDM muscle residues greater than the FDA tolerance (0.1 μg/g) by 48 hours following the final dose.     

Distribution and depletion of flubendazole and its metabolites in edible tissues of guinea fowl

1. We measured the distribution and depletion of residues of flubendazole and its major metabolites in breast muscle, thigh muscle and liver of guinea fowls during and after oral administration of the veterinary medicine Flubenol 5% at two doses. 2. The guinea fowls were treated orally with normal feed, medicated at doses of 56 and 86 mg per kg feed for 7 successive days. Afterwards, depletion was observed for 8 d. Just before slaughter, body weights were measured. Thigh muscle, breast muscle and liver of three female and three male birds were sampled. The concentrations of the flubendazole-derived residues were determined by a liquid chromatographic-mass spectrometric method. 3. The highest residue concentrations were obtained for the reduced metabolite. With the therapeutic dose, the maximum mean residue concentrations obtained for this compound in thigh muscle, breast muscle and liver were 312, 288 and 1043 microg/kg, respectively. The values for flubendazole, the parent molecule, were 114, 108 and 108 microg/kg, respectively. The residues of the hydrolysed metabolite were negligible in the sampled muscle tissues. After 24 h of depletion, the sum of the residues of parent and metabolites in muscle tissue still exceeded 50 microg/kg. After 8 d of depletion, flubendazole-derived residues at low concentrations could still be measured in both muscle tissues and liver. Generally, the disposition of residues in breast and thigh muscle was comparable. 4. The European Union has not established a maximum residue limit (MRL) for flubendazole in edible tissues of guinea fowl. In contrast, the existing MRLs for other bird species are expressed as the sum of parent flubendazole and its hydrolysed metabolites. An estimated withdrawal period of three days will assure residue safety in the edible tissues of guinea fowl treated with flubendazole at therapeutic dose. After this withdrawal period following treatment of the guinea fowl, the residues were approximately constant, very low and far below the established safe MRL level for other bird species.     

Pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole in alpacas

The pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) were studied in six healthy male-castrate alpacas (Lama pacos) after intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP-SMX using a crossover design with a 2-week washout period. After 90 days one group (n = 3) was given a p.o. dose of 30 mg/kg TMP-SMX and the other group (n = 3) was given a p.o. dose of 60 mg/kg TMP-SMX. After i.v. administration of 15 mg/kg of TMP-SMX the mean initial plasma concentration (C0) was 10.75 +/- 2.12 microg/mL for trimethoprim (TMP) and 158.3 +/- 189.3 microg/mL for sulfamethoxazole (SMX). Elimination half-lives were 0.74 +/- 0.1 h for TMP and 2.2 +/- 0.6 h for SMX. The mean residence times were 1.45 +/- 0.72 h for TMP and 2.8 +/- 0.6 h for SMX. The areas under the respective concentration vs. time curves (AUC) were 2.49 +/- 1.62 microg h/mL for TMP and 124 +/- 60 microg h/mL for SMX. Total clearance (Clt) for TMP was 21.63 +/- 9.85 and 1.90 +/- 0.77 mL/min kg for SMX. The volume of distribution at steady state was 2.32 +/- 1.15 L/kg for TMP and 0.35 +/- 0.09 L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak concentration (Cmax) of SMX were 1.9 +/- 0.8, 2.6 +/- 0.4 and 2.8 +/- 0.7 microg/mL, respectively. The AUC was 9.1 +/- 5, 25.9 +/- 3.3 and 39.1 +/- 4.1 microg h/mL, respectively. Based upon these AUC values and correcting for dose, the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not detected in plasma after intragastric administration. These data demonstrate that therapeutic concentrations of TMP-SMX are not achieved after p.o. administration to alpacas.     

Distribution of orally administered trimethoprim and sulfadiazine into noninfected subcutaneous tissue chambers in adult ponies

The distribution of trimethoprim (TMP) and sulfadiazine (SDZ) into subcutaneously implanted noninfected tissue chambers was studied in healthy adult ponies. Six ponies were given an oral TMP/SDZ paste formulation at a dose of 5 mg/kg TMP and 25 mg/kg SDZ at 12 h intervals for 2 days in order to reach steady-state concentrations. Plasma concentrations and tissue chamber fluid (TCF) concentrations of both drugs were measured at regular intervals during a period commencing 24 h after the last oral administration. The peak concentration of TMP (mean +/- SD) was 2.92 +/- 0.86 microg/mL for plasma and 1.09 +/- 0.25 microg/mL for TCF. For SDZ, the mean peak concentration was 40.20 +/- 14.74 microg/mL for plasma and 23.48 +/- 5.84 microg/mL for TCF. TMP peak concentrations in plasma were reached at 3.17 +/- 03.48 h and those in TCF at 7.33 +/- 03.72 h. SDZ peak concentrations in plasma were reached at 1.83 +/- 02.04 h and those in TCF at 8.00 +/- 03.10 h. Concentrations of TMP and SDZ in TCF remained above the generally accepted breakpoint for susceptibility (0.5/9.5 for the TMP/SDZ combination) for 12 h. Therefore, in ponies oral administration of TMP/SDZ at a dose rate of 30 mg/kg given twice daily in the form of a paste should be appropriate for effective treatment of infections caused by susceptible bacteria.     

Pharmacokinetics of voriconazole following intravenous and oral administration and body fluid concentrations of voriconazole following repeated oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of voriconazole following IV and PO administration and assess the distribution of voriconazole into body fluids following repeated PO administration in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURES: All horses received voriconazole (10 mg/kg) IV and PO (2-week interval between treatments). Plasma voriconazole concentrations were determined prior to and at intervals following administration. Subsequently, voriconazole was administered PO (3 mg/kg) twice daily for 10 days to all horses; plasma, synovial fluid, CSF, urine, and preocular tear film concentrations of voriconazole were then assessed. RESULTS: Mean +/- SD volume of distribution at steady state was 1,604.9 +/- 406.4 mL/kg. Systemic bioavailability of voriconazole following PO administration was 95 +/- 19%; the highest plasma concentration of 6.1 +/- 1.4 microg/mL was attained at 0.6 to 2.3 hours. Mean peak plasma concentration was 2.57 microg/mL, and mean trough plasma concentration was 1.32 microg/mL. Mean plasma, CSF, synovial fluid, urine, and preocular tear film concentrations of voriconazole after long-term PO administration were 5.163 +/- 1.594 microg/mL, 2.508 +/- 1.616 microg/mL, 3.073 +/- 2.093 microg/mL, 4.422 +/- 0.8095 microg/mL, and 3.376 +/- 1.297 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that voriconazole distributed quickly and widely in the body; following a single IV dose, initial plasma concentrations were high with a steady and early decrease in plasma concentration. Absorption of voriconazole after PO administration was excellent, compared with absorption after IV administration. Voriconazole appears to be another option for the treatment of fungal infections in horses.     

Pharmacokinetics of lidocaine following the application of 5% lidocaine patches to cats

Lidocaine patches have been used to provide local analgesia in dogs and cats. We conducted this study to assess the systemic and local absorption of lidocaine from topical patches in cats. Eight 2-year-old cats received either intravenous lidocaine at 2 mg/kg or one 700 mg lidocaine patch placed on the lateral thorax for 72 h, in a cross-over randomized repeated measures design. Plasma was collected at specific times and the skin was biopsied at the time of patch removal for the quantitative analysis of lidocaine and its major metabolite, monoethylglycinexylidide (MEGX), by gas chromatography with mass spectrometry. Percent absorption time plots for systemic lidocaine appearance were constructed using the Loo-Riegelman method. Approximately, constant rate absorption was observed from 12-72 h after patch application at a mean +/- SD rate of 109 +/- 49 microg/kg/h, resulting in steady-state lidocaine plasma concentrations of 0.083 +/- 0.032 microg/mL and MEGX concentrations of 0.012 +/- 0.009 microg/mL. Overall bioavailability of transdermal lidocaine was 6.3 +/- 2.7%, and only 56 +/- 29% of the total lidocaine dose delivered by the patch reached systemic circulation. Skin lidocaine concentrations were much higher than plasma concentrations, at 211 +/- 113 microg/g in the thoracic skin beneath the patch and 2.2 +/- 0.6 microg/g in the contralateral thoracic skin without the patch. As both lidocaine and MEGX were recovered from contralateral skin, it is likely that lidocaine accumulated in the skin from low systemic concentrations of circulating lidocaine over the 72-h period of patch application. Plasma lidocaine concentrations remained well below systemically toxic concentrations, and no obvious clinical side effects were observed in any of the cats. The low systemic absorption rate coupled with high local lidocaine concentrations on the skin support the safe use of lidocaine patches in cats.     

Evaluation of the concentration of marbofloxacin in alveolar macrophages and pulmonary epithelial lining fluid after administration in dogs

OBJECTIVE: To determine concentrations of marbofloxacin in alveolar macrophages (AMs) and epithelial lining fluid (ELF) and compare those concentrations with plasma concentrations in healthy dogs. ANIMALS: 12 adult mixed-breed and purebred hounds. PROCEDURE: 10 dogs received orally administered marbofloxacin at a dosage of 2.75 mg/kg every 24 hours for 5 days. Two dogs served as nontreated controls. Fiberoptic bronchoscopy and bronchoalveolar lavage procedures were performed while dogs were anesthetized with propofol, approximately 6 hours after the fifth dose. The concentrations of marbofloxacin in plasma and bronchoalveolar fluid (cell and supernatant fractions) were determined by use of high-performance liquid chromatography with detection of fluorescence. RESULTS: Mean +/- SD plasma marbofloxacin concentrations 2 and 6 hours after the fifth dose were 2.36 +/- 0.52 microg/mL and 1.81 +/- 0.21 microg/mL, respectively. Mean +/- SD marbofloxacin concentration 6 hours after the fifth dose in AMs (37.43 +/- 24.61 microg/mL) was significantly greater than that in plasma (1.81 +/- 0.21 microg/mL) and ELF (0.82 +/- 0.34 microg/mL), resulting in a mean AM concentration-to-plasma concentration ratio of 20.4, a mean AM:ELF ratio of 60.8, and a mean ELF-to-plasma ratio of 0.46. Marbofloxacin was not detected in any samples from control dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Marbofloxacin concentrations in AMs were greater than the mean inhibitory concentrations of major bacterial pathogens in dogs. Results indicated that marbofloxacin accumulates in AMs at concentrations exceeding those reached in plasma and ELF The accumulation of marbofloxacin in AMs may facilitate treatment for susceptible intracellular pathogens or infections associated with pulmonary macrophage infiltration.     

The comparative plasma pharmacokinetics of intravenous cefpodoxime sodium and oral cefpodoxime proxetil in beagle dogs

The pharmacokinetic properties of cefpodoxime, and its prodrug, cefpodoxime proxetil, were evaluated in two separate studies, one following intravenous (i.v.) administration of cefpodoxime sodium and the second after oral (p.o.) administration of cefpodoxime proxetil to healthy dogs. After cefpodoxime administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). A single i.v. administration of cefpodoxime sodium at a dose of 10 mg cefpodoxime/kg body weight resulted in a cefpodoxime average maximum plasma concentration (Cmax) of 91 (+/-17.7) microg/mL, measured at 0.5 h after drug administration, an average half-life (t1/2) of 4.67 (+/-0.680) h, an average AUC(0-infinity) of 454 (+/-83.1) h.microg/mL, an average V(d(ss)) of 151 (+/-27) mL/kg, an average Cl(B) of 22.7 (+/-4.2) mL/h/kg and an average MRT(0-infinity) of 5.97 (+/-0.573) h. When dose normalized to 10 mg cefpodoxime/kg body weight, cefpodoxime proxetil administered orally resulted in Cmax of 17.8 +/- 11.4 microg/mL for the tablet formulation and 20.1 +/- 6.20 microg/mL for the suspension formulation and an average AUC(0-LOQ) of 156 (+/-76.1) h.microg/mL for the tablet formulation and 162 (+/-48.6) h.microg/mL for the suspension formulation. Relative bioavailability of the two oral formulations was 1.04 (suspension compared with tablet), whereas the absolute bioavailability of both oral formulations was estimated to be approximately 35-36% in the cross-study comparison with the i.v. pharmacokinetics. Combined with previous studies, these results suggest that a single daily oral dose of 5-10 mg cefpodoxime/kg body weight as cefpodoxime proxetil maintains plasma concentrations effective for treatment of specified skin infections in dogs.     

Pharmacokinetics of potassium bromide in adult horses

OBJECTIVE: To determine the pharmacokinetics of potassium bromide (KBr) in horses after single and multiple oral doses. ANIMALS: Twelve adult Standardbred and Thoroughbred mares. PROCEDURE: Horses were randomly assigned to two treatment groups. Group 1 horses were given a single oral dose of 120 mg/kg potassium bromide. Part 2 of the study evaluated a loading dose of 120 mg/kg KBr daily by stomach tube for 5 days, followed by 40 mg/kg daily in feed for 7 days. Serum concentrations of KBr were measured to construct concentration versus time curves and to calculate pharmacokinetic parameters. Treated horses were monitored twice daily by clinical examination. Serum concentrations of sodium, potassium and chloride ions and partial pressures of venous blood gases were determined. RESULTS: Maximum mean serum concentration following a single dose of KBr (120 mg/kg) was 423 +/- 22 microg/mL and the mean elimination half-life was 75 +/- 14 h. Repeated administration of a loading dose of KBr (120 mg/kg once daily for 5 d) gave a maximum serum concentration 1639 +/- 156 microg/mL. The administration of lower, maintenance doses (40 mg/kg once daily) was associated with decreased serum bromide concentrations, which plateaued at approximately 1000 microg/mL. Administration of KBr was associated with significant but transient changes in serum potassium and sodium concentrations, and possible changes in base excess and plasma bicarbonate concentrations. High serum concentrations of bromide were associated with an apparent increase in serum chloride concentrations, when measured on an ion specific electrode. CONCLUSIONS: and clinical relevance Loading doses of 120 mg/kg daily over 5 d and maintenance doses of approximately 90 mg/kg of KBr administered once daily resulted in serum bromide concentrations consistent with therapeutic efficacy for the management of seizures in other species. The clinical efficacy of this agent as an anticonvulsant medication and/or calmative in horses warrants further investigation.     

Pharmacokinetics of amoxycillin and the rate of depletion of its residues in pigs

Six pigs were used in a two-period crossover study to investigate the pharmacokinetics of amoxycillin after single intravenous and oral doses of 20 mg/kg bodyweight. Twelve pigs were used to study the residues of the drug in muscle, kidney, liver and fat after they had received daily oral doses of 20 mg/kg amoxycillin for five days. The mean (sd) elimination half life (t1/2beta) and mean residence time of amoxycillin in plasma were 3.38 (0.30) and 3.54 (0.43) hours, respectively, after intravenous administration and 4.13 (0.50) and 4.47 (0.30) hours, respectively, after oral administration. After oral administration, the maximum plasma concentration (Cmax) was 7.37 (0.42) microg/ml and it was reached after 0.97 (0.29) hours. Six days after the last oral dose, the mean concentration of amoxycillin in the pigs' kidneys was 21.38 ng/g and in the liver it was 12.32 ng/g, but no amoxycillin could be detected in fat or muscle; the concentrations of amoxycillin in edible tissues were less than the European Union maximal residue limit of 50 microg/kg.     

Ceftiofur distribution in plasma and tissues following subcutaneously administration in ducks

A study was performed to determine the residues in blood and edible tissues of healthy ducks (25 days old, mean body weight 1.0+/-0.13 kg) after subcutaneous administration of ceftiofur sodium at a dose rate of 2 mg/kg body weight (Group I) and 4 mg/kg body weight (Group II). Blood, muscle, liver, kidney, and fat samples were collected from all of ducks on the 1st, 2nd, 3rd, 4th, and 5th day after treatment of drug, and ceftiofur was analyzed with a high-performance liquid chromatography (HPLC) assay with results reported as ceftiofur-free acid equivalent (CFAE). To study the spiked recovery, blank plasma and tissues were spiked with two different concentrations of ceftiofur sodium (0.1, 0.5 microg/g). Average recovery values for all samples ranged from 70.3 to 87.3%. In the group I, desfuroylceftiofur acetamide (DCA) was not detected in all of plasma, muscle, liver, and fat tissues on the 1st day after treatment. But, kidney samples on the 1st day were detected DCA (0.059+/-0.01 microg CFAE/g tissue). On the 2nd day of post-treatment, the concentrations of DCA in all tissues were lower than the detection limit, 0.05 microg CFAE /g tissue. In the group II on the 1st day after treatment, the concentration of DCA was 0.124+/-0.06 microg CFAE/g tissue, 0.103+/-0.03 microg CFAE/g tissue, and 0.071+/-0.010 microg CFAE/g tissue in plasma, kidney, and muscle samples, respectively. On the 2nd day after treatment of ceftiofur, the concentrations of DCA in all tissues were lower than 0.05 microg CFAE/g tissue. According to our results, the concentrations of DCA on the 1st day after treatment with 2 mg/kg body weight were below 0.05 microg CFAE/g tissue equivalent in all tissues except for kidney. On the 2nd day after administration at the dose of 4 mg/kg body weight, no DCA was also detected in all of the tissues although DCA was detected in all samples on the 1st day.     

Effect of oral administration of dantrolene sodium on serum creatine kinase activity after exercise in horses with recurrent exertional rhabdomyolysis

OBJECTIVE: To determine the effect of oral administration of dantrolene sodium on serum creatine kinase (CK) activity after exercise in horses with recurrent exertional rhabdomyolysis (RER). ANIMALS: 2 healthy horses and 5 Thoroughbreds with RER. PROCEDURE: 3 horses received 2 doses of dantrolene (4, 6, or 8 mg/kg, p.o., with and without withdrawal of food) 2 days apart; 90 minutes after dosing, plasma dantrolene concentration was measured spectrofluorometrically. On the basis of these results, 5 Thoroughbreds with RER from which food was withheld received dantrolene (4 mg/kg) or an inert treatment (water [20 mL]) orally 90 minutes before treadmill exercise (30 minutes, 5 d/wk) during two 3-week periods. Serum CK activity was determined 4 hours after exercise. Plasma dantrolene concentration was measured before and 90 minutes after dosing on the first and last days of dantrolene treatment and before dosing on the first day of the inert treatment period, RESULTS: 90 minutes after dosing, mean +/- SEM plasma dantrolene concentration was 0.62 +/- 0.13 and 0 microg/mL in the dantrolene and inert treatment groups, respectively. Serum CK activity was lower in dantrolene-treated horses (264 +/- 13 U/L), compared with activity in water-treated horses (1,088 +/- 264 U/L). Two horses displayed marked muscle stiffness on the inert treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In 5 horses with RER from which food had been withheld, 4 mg of dantrolene/kg administered orally provided measurable, though variable, plasma concentrations and significantly decreased serum CK activity after exercise in 4 of those horses.     

Dispositions and residue depletion of enrofloxacin and its metabolite ciprofloxacin in muscle tissue of giant freshwater prawns (Macrobrachium rosenbergii)

Fates and residue depletion of enrofloxacin (ER) and its metabolite ciprofloxacin (CP) were examined in giant freshwater prawns, Macrobrachium rosenbergii, following either single oral (p.o.) administration of ER at a dosage of 10 mg/kg body weight (b.w.) or medicated‐feed treatment at the feeding concentration of 5 g/kg of feed for five consecutive days. The concentrations of ER and CP in prawn muscle tissues were measured simultaneously using high‐performance liquid chromatography (HPLC) equipped with a fluorescence detector. Muscle tissue concentrations of ER and CP were below the detection limit (LOD, 0.015 μg/g for ER; 0.025 μg/g for CP) after 360 and 42 h, following single p.o. administration respectively. Peak muscle concentration (C_max) of ER was 1.98 ± 0.22 μg/g whereas CP was measurable at concentrations close to the detection limit of the analytical method after p.o. administration at a single dosage of 10 mg/kg b.w. The concentration of ER in prawn muscle tissue with respect to time was analyzed with a non‐compartmental pharmacokinetic model. The elimination half‐life and area under the curve of ER were 39.33 ± 7.27 h and 168.7 ± 28.7 μg·h/g after p.o. administration at a single dose of 10 mg/kg·b.w. respectively. In medicated‐feed treated group, ER was detectable in prawn muscle tissue 11 days postdosing at the dose of 5 g/kg of feed for five consecutive days, which is the value corresponding to the maximum residue limit (MRL) of ER in animal products. The maximum concentrations of ER and CP were 2.77 ± 0.91 and 0.06 ± 0.006 μg/g during medicated‐feed treatment and postdosing respectively. The values of elimination half‐life and absorption half‐life of ER after single p.o. administration at a dosage of 10 mg/kg b.w. corresponded well with the values determined from medicated‐feed treated group, showing 41.01 ± 6.62 and 11.36 ± 3.15 h respectively in M. rosenbergii. Based on data derived from this study, to avoid the ER residue in prawn muscle, it should take at least 11 days postcessation of medicated feed containing ER at the dose concentration of 5 g/kg of feed twice a day at a rate of 1% of total body weight for five consecutive days to wash out the drug from the muscle of M. rosenbergii.     

Pharmacokinetics and tissue residues of pefloxacin and its metabolite norfloxacin in broiler chickens

1. The pharmacokinetics of pefloxacin and its active metabolite norfloxacin were investigated in chickens after a single oral administration of pefloxacin at a dosage of 10 mg/kg. To characterise the residue pattern, another group of chickens was given 10 mg of pefloxacin/kg body once daily for 4 d by oral route; the tissue concentrations of pefloxacin and norfloxacin were determined at 1, 5 and 10 d after the last administration of the drug. 2. The concentrations of pefloxacin and norfloxacin in plasma and tissues were determined by HPLC assay. The limit of detection for pefloxacin and norfloxacin was 0.03 microg/ml in plasma or microg/g in tissue. 3. The plasma concentration-time data for pefloxacin and norfloxacin were characteristic of a one-compartment open model. The elimination half-life, maximum plasma drug concentration, time to reach maximum plasma drug concentration and mean residence time of pefloxacin were 8.74 +/- 1.48 h, 3.78 +/- 0.23 microg/ml, 3.33 +/- 0.21 h and 14.32 +/- 1.94 h, respectively, whereas the respective values of these variables for norfloxacin were 5.66 +/- 0.81 h, 0.80 +/- 0.07 microg/ml, 3.67 +/- 0.21 h and 14.44 +/- 0.97 h. 4. Pefloxacin was metabolised to norfloxacin to the extent of 22%. 5. The concentrations of pefloxacin (microg/g) 24 h after the fourth dose of the drug declined in the following order: liver (3.20 +/- 0.40) > muscle (1.42 +/- 0.18) > kidney (0.69 +/- 0.04) > skin and fat (0.06 +/- 0.02). Norfloxacin was also detectable in all the tissues analysed except muscle. No drug and/or its metabolite was detectable in tissues except skin and fat 5 d after the last administration. The concentrations of pefloxacin and norfloxacin in skin and fat 10 d after the last dose of pefloxacin were 0.04 +/- 0.02 and 0.03 +/- 0.01 microg/g, respectively.     

Pharmacokinetics of once-daily amikacin in healthy foals and therapeutic drug monitoring in hospitalized equine neonates

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P <.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C0.5h) were significantly higher (P = .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 microg/mL, suggesting that amikacin C0.5h of 40 microg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C0.5h 40 microg/mL was significantly higher (P < .0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24h concentrations > or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.     

Accumulation and elimination of enrofloxacin and its metabolite ciprofloxacin in the ridgetail white prawn Exopalaemon carinicauda following medicated feed and bath administration

Accumulation and elimination of enrofloxacin and its metabolite ciprofloxacin were evaluated in Exopalaemon carinicauda following medicated feed at dose of 10 mg/kg weight body per day for five consecutive days and 10 mg/L bath for five consecutive days at 18 °C. At different times, nine ridgetail white prawns were randomly selected from the tank and sampled after the last medicated feed or bath administration. The concentration of enrofloxacin and ciprofloxacin in the main tissues (hepatopancreas, muscle, gill, and ovary) was detected by HPLC. The results showed that the maximum concentrations of enrofloxacin were 3.408 ± 0.245, 0.554 ± 0.088, 0.789 ± 0.074, and 0.714 ± 0.123 μg/g for hepatopancreas, muscle, gill, and ovary, respectively, at 1 day after the last medicated feed treatment. The enrofloxacin concentrations were 2.389 ± 0.484, 0.656 ± 0.012, 0.951 ± 0.144, and 3.107 ± 0.721 μg/g in hepatopancreas, muscle, gill, and ovary, respectively, at 1 day after the last bath administration. Ciprofloxacin could be detected in hepatopancreas, muscle, gill, and ovary. However, the concentrations of ciprofloxacin were much lower in comparison with that of enrofloxacin in various tissues. The concentrations of enrofloxacin plus ciprofloxacin in hepatopancreas, muscle, gill, and ovary followed an eliminating pattern during the sampling time after the two routes of administration. Based on data derived from this study, to avoid the enrofloxacin and ciprofloxacin residue in E. carinicauda, it should take at least 20 and 25 days to wash out the drug from the tissues after the last medicated feed and bath administration with enrofloxacin, respectively. These results helped the Chinese fishery department to lay down the current guidelines on enrofloxacin plus ciprofloxacin withdrawal periods for farmed shrimp.     

Determination of sulfadiazine,trimethoprim, and N4‐acetyl‐sulfadiazine in fish muscle plus skin by Liquid Chromatography–Mass Spectrometry. Withdrawal‐time calculation after in‐feed administration in gilthead sea bream (Sparus aurata L.) fed two different diets

This study presents a depletion study for sulfadiazine and trimethoprim in muscle plus skin of gilthead sea bream (Sparus aurata L.). N⁴‐acetyl‐sulfadiazine, the main metabolite of sulfadiazine (SDZ), was also examined. The fish were held in seawater at a temperature of 24–26 °C. SDZ and trimethoprim (TMP) were administered orally with medicated feed for five consecutive days at daily doses of 25 mg SDZ and 5 mg TMP per kg of fish body weight per day. Two different diets, fish oil‐ and plant oil‐based diets, were investigated. Ten fish were sampled at each of the days 1, 3, 5, 6, 8, 9, 10, and 12 after the start of veterinary medicine administration. However for the calculation of the withdrawal periods, sampling day 1 was set as 24 h after the last dose of the treatment. Fish samples were analyzed for SDZ, TMP, and acetyl‐sulfadiazine (AcSDZ) residues by liquid chromatography–mass spectrometry. SDZ and TMP concentrations declined rapidly from muscle plus skin. Considering a maximum residue limit of 100 μg/kg for the total of sulfonamides and 50 μg/kg for TMP residues in fish muscle plus skin, the withdrawal periods of the premix trimethoprim‐sulfadiazine 50% were calculated as 5 and 6 days, at 24–26 °C, in fish oil (FO) and plant oil (PO) groups, respectively. The investigation of this work is important to protect consumers by controlling the undesirable residues in fish.