Pharmacokinetics of oxytetracycline after intramuscular administration with lidocaine in sheep, comparison with a conventional formulation

The pharmacokinetic behaviour of oxytetracycline (OTC) was studied in 11 sheep after intravenous and intramuscular administration at a single dosage of 20 mg kg⁻¹ bodyweight. A conventional formulation was injected by the intravenous route and two different preparations were administered by the intramuscular route: a conventional formulation (T-100) and an aqueous solution of OTC with lidocaine (1 per cent) (OTC-Q. The objective was to determine whether there are differences between both formulations in the disposition kinetics of OTC after intramuscular administration to sheep. After intravenous administration of the conventional formulation, plasma oxytetracycline concentrations were best fitted to an open two-compartment model. Mean apparent volume of distribution was 0·77±0·02 litre kg⁻¹ and the harmonic mean half-life was three hours. The OTC transfer process between central and peripheral compartments was fast and that did not influence the elimination process. After intramuscular administrations of both formulations, half-lives were longer than after intravenous administration (mean values of 14·1 and 58·2 hours for T-100 and OTC-L respectively). In both cases, a biphasic absorption, a ‘flip-flop’ model and a complete bioavailability were found. OTC-L provided therapeutic plasma concentrations over 0·5 μg ml⁻¹ (the minimum inhibitory concentration for most susceptible pathogens) for a longer period of time than T-100 (72 hours compared with 36 or 48 hours).     

Pharmacokinetics and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats

The pharmacokinetic profile and bioavailability of a long-acting formulation of cephalexin after intramuscular administration to cats was investigated. Single intravenous (cephalexin lysine salt) and intramuscular (20% cephalexin monohydrate suspension) were administered to five cats at a dose rate of 10 mg/kg. Serum disposition curves were analyzed by noncompartmental approaches. After intravenous administration, volume of distribution (V_z), total body clearance (Cl_t), elimination constant (λ_z), elimination half-life (t_½λ) and mean residence time (MRT) were: 0.33 ± 0.03 L/kg; 0.14 ± 0.02 L/h kg, 0.42 ± 0.05 h⁻¹, 1.68 ± 0.20 h and 2.11 ± 0.25 h, respectively. Peak serum concentration (C_max), time to peak serum concentration (T_max) and bioavailability after intramuscular administration were 15.67 ± 1.95 μg/mL, 2.00 ± 0.61 h and 83.33 ± 8.74%, respectively.     

Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparation

The pharmacokinetics of a long‐acting oxytetracycline (OTC) formulation (Liquamycin® LA‐200®) injected intramuscularly (i.m.) at a dose of 20 mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168±14.6 (μg ? h/mL) and was significantly less than the AUC for sheep (209±43 μg ? h/mL). Using the standard two‐stage approach and a one‐compartment model, the mean Cmax for the calves was 5.2±0.8 μg/mL, and for the sheep was 6.1±1.3 μg/mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08 L/kg for the calves and sheep respectively. Analysis of the data using the standard two‐stage approach, the naive pooled‐data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20 mg/kg OTC. Half‐lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9 h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6 p.p.m.), muscle (2 p.p.m.) and kidney (12 p.p.m.) by 48 h, and in injection site muscle by 14 days after the single i.m. injection of 20 mg/kg.     

Some pharmacokinetic parameters of doxycycline in East African goats after intramuscular administration of a long-acting formulation

A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employingBacillus cereus varmycoides (ATCC 11778) as the test organism. The mean serum concentration (C _max) and the time of maximum concentration (T _max) were 1.87 µg/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h.The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.41 h. The mean values for the volume of distribution at steady state (V _dss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared.It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.Abbreviations ATCC American Type Culture Collection - AVC total area under the plasma concentration-time curve - AUMC area under the curve of the product from time zero to infinity - C1 total body clearance - i.m. intramuscular - i.v. intravenous - MRT mean residence time - MIC minimum inhibitory concentration - PVP polyvinyl pyrolidone - V_d volume of distribution - V _dss volume of distribution at steady state     

Pharmacokinetics of cefonicid in lactating goats after intravenous,intramuscular and subcutaneous administration,and after a long-acting formulation for subcutaneous administration

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (V_ss) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.     

两种头孢噻呋注射液在猪体内的比较药动学研究

研究了两种头孢噻呋注射液给猪肌注后的比较药物动力学特征。选用12头健康猪随机分为两组,每组6头,分别肌注上海公谊兽药厂生产的长效盐酸头孢噻呋注射液和美国辉瑞生产的盐酸头孢噻呋注射液（速解灵注射液）,每头5mg／kg。采用超高效液相色谱法测定猪血浆中头孢噻呋的的药物浓度,用Winnonlin5．2药动学分析软件非房室模型处理药时数据,模型200处理肌注给药后的药代动力学参数。结果表明：健康猪肌注两种注射液后,参数MRT、Cmax、tmax统计差异极显著（P〈0．01）,长效盐酸头孢噻呋注射液单剂量肌注给药较速解灵注射液吸收慢,达峰时间显著延迟,达峰浓度显著降低,平均驻留时间显著延长;参数AUC、Kel、t1/2允统计无显著性差异（P〉0．05）,长效盐酸头孢噻呋注射液的相对生物利用度为98．41％,与速解灵注射液的生物利用度相当。本研究可为头孢噻呋注射液的临床合理用药提供参考。     

Pharmacokinetics of sodium amoxicillin in foals after intramuscular administration

Pharmacokinetic values of sodium amoxicillin (22 mg/kg of body weight) in foals were determined after a single IM injection in 6 Quarter Horse foals at 3, 10, and 30 days of age. Serum amoxicillin concentrations were measured serially over a 24-hour period. The absorption of amoxicillin was rapid and followed a 1st-order elimination. Mean peak serum concentrations occurred 30 minutes after the injection in foals at all ages and were 17.31 +/- 9.59 micrograms/ml when the foals were 3 days old, 23.28 +/- 9.86 micrograms/ml when the foals were 10 days old, and 21.35 +/- 6.39 micrograms/ml when the foals were 30 days old. Serum samples collected beyond 8 hours after administration contained amoxicillin concentrations less than 0.05 micrograms/ml. The elimination rate constant increased with increasing age (0.5265 +/- 0.0891 hour-1 when the foals were 3 days old, 0.6494 +/- 0.1114 hour-1 when the foals were 10 days old, and 0.7112 +/- 0.1016 hour-1 when the foals were 30 days old). Serum clearance increased with increasing age (498.4 +/- 82.6 ml/hr/kg at 3 days, 631.6 +/- 170.5 ml/hr/kg at 10 days, and 691.2 +/- 127.3 ml/hr/kg at 30 days). Serum half-life decreased with increasing age (1.34 +/-0.243 hour at 3 days, 1.10 +/- 0.239 hour at 10 days, and 0.991 +/- 0.139 hour at 30 days), whereas the extrapolated concentration at time zero and apparent volume of distribution did not change during the first 30 days of age.     

Comparative pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous administration to sheep and goats

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination was studied after intravenous administration of single doses (20 mg/kg per kg body weight) to five sheep and six goats. The objective was to determine whether there are differences between sheep and goats in the disposition of amoxicillin and clavulanic acid. The plasma concentration-time data were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in sheep and goats. The elimination half-lives of amoxicillin were 1.43 ± 0.16 h in sheep and 1.13 ± 0.19 h in goats, and of clavulanic acid were 1.16 ± 0.01 h and 0.85 ± 0.09 h in sheep and goats respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. Body clearances of amoxicillin were 0.09 ± 0.01 L/h kg in sheep and 0.11 ± 0.01 L/h kg in goats, and of clavulanic acid were 0.07 ± 0.01 L/h kg and 0.12 ± 0.01 L/h kg in sheep and goats respectively. The half-lives and body clearances of amoxicillin and clavulanic acid differed significantly between sheep and goats. It was concluded that the disposition of amoxicillin and clavulanic acid administered intravenously as an amoxicillin/clavulanic acid combination to sheep and goats differed between the two ruminant species. Even though the differences in disposition kinetics of both drugs were statistically significant, the same intravenous dosing rate of this antimicrobial combination can generally be used in sheep and goats.     

Determination of milk/plasma ratio and milk and plasma pharmacokinetics of amoxicillin after intramuscular administration in lactating cows

This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmacokinetics in milk and plasma after intramuscular administration. Five healthy dairy cows (Holstein, weighing 450–500 kg, aged 2–4 years) were used in this study. They received single intramuscular amoxicillin at a dose of 14 mg/kg body weight. Blood and milk samples were collected prior to drug administration (0); after 15, 30, 45, 60, and 90 min; and 2, 3, 4, 6, 8, 10, and 12 hr after administration. The plasma and milk concentrations of amoxicillin were determined using high‐performance liquid chromatography with ultraviolet detection. The passage ratio of amoxicillin into milk and plasma was determined using both AUC‐based calculation and milk and plasma concentrations at sampling times; it was calculated 0.46 and 0.52, respectively. The terminal half‐life and mean residence time of amoxicillin were 6.05 and 8.60 hr in plasma and 2.62 and 5.35 hr in milk, respectively. The C_max2 levels of amoxicillin in plasma and milk were measured as 1,096 and 457 ng/ml, respectively. It was observed that amoxicillin exhibited a secondary peak in plasma and milk. This study was the first to report on the passage ratio of amoxicillin into milk in lactating cows.     

Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs

He, J., Tang, S., Li, L., Zhang, C., Li, X., Xia, X., Xiao, X. Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs. J. vet. Pharmacol. Therap. 34 , 42–50. An amoxicillin (AMO) or colistin (COS) oil suspension was developed and corresponding pharmacokinetics studies were conducted in pigs after i.m. injection. The combination product is a white‐ to cream‐colored oil suspension which is easy to be re‐dispersed. Settling volume ratio, syringeability and flowability of the product is well consistent with the technical standards set by the Ministry of Agriculture of People’s Republic of China. Two studies were conducted to investigate the pharmacokinetics of the combination product in swine. First, the pharmacokinetics of the combination product was compared with those of the same products merely removing either AMO or COS. No significant change in the major pharmacokinetic parameters (C_max, T_max, MRT, t_1/2λ, AUC and AUMC) was observed when either component was removed from the combination product, indicating that AMO and COS do not interfere with each other in their absorption and distribution in the tissue when used as a combination. Second, the pharmacokinetics of the combination product was compared with that of their respective single products. It was found that the apparent elimination half‐lives (t_1/2λ) of AMO and COS in combination product were 6.38 and 8.09 h, which were 2.40 and 2.38 times longer than the single products, respectively. Thus, the novel AMO/COS suspension extended significantly the half‐life of both drugs to maintain a longer drug residence time in pigs when compared to their single products.     

Tissue damage at the injection site after intramuscular injection of drugs

Tissue damage at the injection site has been described after intramuscular injection of antibiotics, chemotherapeutics, vitamins, lidocaine, diazepam and digoxin in dogs, swine, cows, sheep and hens.The damage caused by substances commonly used in drug vehicles has also been examined and compared with the effects of saline and distilled, sterile water. After intramuscular injection of saline or sterile water little or no tissue reaction has been observed, while vehicles containing glycerol formal or propylene glycol caused damage to muscle tissue.The investigations show that both the drug itself and the vehicles may cause tissue damage. In the development of drug preparations for intramuscular administration, which cause minimal tissue damage, it is therefore important to consider all the components of the preparation.From the point of view of international collaboration it will be of great importance that standard methods are generally accepted for the evaluation of new drugs and for the estimation and prediction of tissue damage after their intramuscular injection.

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Kurzfassung Gewebeschäden an der Injektionsstelle liessen sich nach der intramuskulären Verabreichung von u. a. Antibiotika, chemotherapeutischen Erzeugnissen, Vitaminpräparaten, Lidokain, Diazepam und Digoxin bei Hunden, Schweinen, Kühen, Schafen oder Hühnern feststellen.Dabei wurde die irritierende Wirkung der üblicherweise in den Bindemitteln enthaltenen Substanzen untersucht und mit der Wirkung von salinem und destilliertem, sterilem Wasser verglichen. Bindemittel, die Formalglyzerin oder Propylenglykol enthalten, verursachten eine Schädigung des Muskelgewebes.Die erwähnten Untersuchungen ergaben, dass sowohl das Medikament selbst, als auch das Bindemittel Gewebeschäden hervorrufen können. Daher ist bei der Entwicklung von Arzneimitteln, deren gewebeschädigende Wirkung bei intramuskulärer Verabreichung minimal sein soll, darauf zu achten, dass alle Bestandteile des Präparates geprüft werden.Für eine internationale Zusammenarbeit dürfte es von grosser Bedeutung sein, dass die unterschiedlichen Bewertungsmethoden für neue Medikamente allgemeingültig festgelegt werden; dies gilt auch für die Einschätzung oder vorherige Bestimmung der lokalen Schädigung durch die intramuskuläre Injektion.

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Resume L'effet de lésion tissulaire au point d'injection a été décrit après l'injection intramusculaire d'antibiotiques, de chimiothérapeutiques, de vitamines, lidocaine, diazepam et digoxine chez des chiens, porcs, moutons ou poules. L'effet d'irritation des substances communément utilisées dans les excipients a été examiné et comparé à l'effet de l'eau salée et distillée ou de l'eau sterile. Les excipients contenant du glycérol formaldéhyde ou du propylène glycol ont provoqué des lésions du tissu musculaire.Les études citées révèlent que le médicament lui-même comme les excipients peuvent provoquer des lésions tissulaires. Aussi fautil tenir compte, pour la mise au point de préparations pharmaceutiques pour l'administration par voie intramusculaire ne causant qu'une lésion minimale des tissus, de tous les composants entrant dans la préparation.Du point de vue de la collaboration internationale, il sera très important que les différentes méthodes d'évaluation des nouveaux médicaments soient unanimement acceptées ainsi que les méthodes utilisées pour l'estimation ou la prédiction de lésions locales après injection intramusculaire.

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Riassunto Viene descritta l'azione lesiva osservata nei tessuti nel punto di inoculazione per via intramuscolare dei farmaci per uso veterinario, quali antibiotici, chemioterapici, vitamine, lidocaina, diazepam e digoxin. Le osservazioni sono state eseguite su cani, suini, bovini, ovini, o polli.L'effetto irritante di sostanze d'uso comune in eccipienti farmaceutici è stato confrontato con l'effetto dell'acqua distillata sterile e della soluzione fisiologica, pure sterile.Gli eccipienti contenenti glicerina o glicole propilenico hanno provocato lesioni nel tessuto muscolare. Dalle indagini descritte appare evidente che sia il farmaco che gli eccipienti possono provecare danni ai tessuti. Pertanto, al fine di migliorare i preparati farmaceutici per somministrazione intramuscolare che possono provocare lesioni anche minime nei tessuti, è importante prendere in considerazione tutti i componenti dei preparati stessi.Dal punto di vista di una collaborazione internazionale, è di grande importanza che i vari metodi di esame dei nuovi farmaci siano unanimente accettati, compresi i metodi untilizzati per l'esame e la prevenzione dei danni locali conseguenti alla inoculazione per via intramuscolare.

     

Bioavailability of levamisole after intramuscular and oral administration in sheep

AIMS: To determine the bioavailability of levamisole in sheep. METHODS: Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at 20 degrees C until analysed. The levamisole concentration in plasma was determined by high performance liquid chromatography with a U.V. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. RESULTS: The values obtained for k(a), C(max), t(max) and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25-33% higher and C(max) two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects k(a), C(max), t(max) and F; significant differences were found in these parameters. CLINICAL RELEVANCE: On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.     

Pharmacokinetics of indomethacin in sheep after intravenous and intramuscular administration

The pharmacokinetics of indomethacin (1mg/kg) was determined in six adult sheep after intravenous (i.v.) and intramuscular (i.m.) injection. Plasma concentrations were maintained within the therapeutic range (0.3–3.0 μg/mL) from 5 to 50 min after i.v. and from 5 to 60–90 min after i.m. administration. After two trials, indomethacin best fitted an open two-compartment model. The mean (±SD) volumes of distribution at steady state ( V d_ss) were 4.10 ± 1.40 and 4.21 ± 1.93 L/kg and the mean clearance values ( C l_B) were 0.17 ± 0.06 and 0.22 ± 0.12 L/h.kg for i.v. and i.m. routes, respectively. The elimination phase half-lives did not show any significant difference between routes of injection ( t _½β = 17.4 ± 4.6 and 21.25 ± 4.44 h, i.v. and i.m. respectively). After i.m. administration, plasma maximum concentration ( C _max =  1.10 ± 0.68 μg/mL) was reached 10 min after dosing; the absorption phase was fast ( K _ab = 26 ± 18 h-1) and short ( t _½ab = 2.33 ± 1.51 min) and the mean bioavailability was 91.0 ± 32.8%, although there was considerable interanimal variation. In some individuals, bioavailability was higher than 100%. This fact combined with the slower elimination phase after i.m. than after i.v. administration, could be related with enterohepatic recycling.     

Population pharmacokinetics of ceftazidime after a single intramuscular injection in wild turtles

Ceftazidime, a third‐generation cephalosporin, is important for treating opportunistic bacterial infections in turtles. Antibacterial dosage regimens are not well established for wild turtles and are often extrapolated from other reptiles or mammals. This investigation used a population pharmacokinetic approach to study ceftazidime in wild turtles presented for rehabilitation. Ceftazidime was administered to 24 wild turtles presented to the Turtle Rescue Team at North Carolina State University. A sparse blood sampling protocol was used to collect samples from 0 to 120 hr with three samples per individual after injection. Plasma samples were analyzed by high‐pressure liquid chromatography (HPLC). A nonlinear mixed‐effects model (NLME) was fitted to the data to determine typical values for population parameters. We identified a long half‐life (T½) of approximately 35 hr and volume of distribution (V_SS) of 0.26 L/kg. We concluded that this long T½ will allow for a dose of 20 mg/kg injected IM to maintain concentrations above the MIC of most wild‐type bacteria for 5 days. Because of long intervals between injections, stability of stored formulations was measured and showed that 90% strength was maintained for 120 hr when stored in the refrigerator and for 25 days when stored in the freezer.     

Serum and tissue concentrations of doxycycline in broilers after the sub-cutaneous injection of a long-acting formulation

1. The antibacterial agent doxycycline hyclate (Dox) is usually administered to broilers in drinking water or as a feed supplement. Parenteral injection is not the usual route for administration, so a long-acting formulation (Dox-LA) was tested to evaluate if serum concentrations can achieve the pharmacokinetic/pharmacodynamic (PK/PD) ratios regarded as adequate for the drug.

2. A poloxamer-based matrix was used to provide Dox-LA. Serum and tissue concentrations of Dox vs time were determined in two day-old broilers after subcutaneous (SC) injection of Dox-LA or oral administration of a single bolus of aqueous Dox (Dox-PO), at a dose of 20?mg/kg. Weight gain, feed conversion rate, haematological variables, aspartate aminotransferase and alanine aminotransferase activities, blood urea and creatinine were determined and compared for Dox-LA with Dox-PO and non-medicated controls.

3. Dox-LA had a high relative bioavailability (1200%). Maximum serum concentrations were not statistically different (5·1?±?1·1?µg/ml for Dox-LA and 6·1?±?1.4?µg/ml for Dox-PO), but half-life of Dox-LA was much greater than the value obtained for Dox-PO (73·0?±?0·9?h and 2·0?±?0·02?h, respectively). Tissue concentrations were higher, and stayed higher for longer periods in the Dox-LA group.

4. In conclusion, considering the minimum effective serum concentration against Mycoplasma spp is 0·5?µg/ml, a dose-interval of 180?h can be achieved with Dox-LA, but only for 24?h after Dox-PO. Better PK/PD ratios for Dox-LA should result in improved clinical outcomes compared with Dox-PO.