Pharmacokinetics of florfenicol after treatment of pigs with single oral or intramuscular doses or with medicated feed for three days

The pharmacokinetics of florfenicol, a structural analogue of thiamphenicol, were studied in six pigs after single oral and intramuscular doses of 15 mg/kg bodyweight, and after feeding them with medicated feed containing 250 mg/kg for three days, a concentration which provided approximately the same dose rate of the drug. The oral doses contained a specially prepared pelleted formulation of the drug. The bioavailability of the drug was similar for the oral and intramuscular doses. Florfenicol was absorbed rapidly from the feed and its concentration in plasma remained between 2 and 6 microg/ml - above the minimum inhibitory concentration values for common pig pathogens - during the three days.     

氟苯尼考在猪的群体药动学

收集临床消化道和呼吸道细菌性疾病猪 2 15头 ,其中原种猪 91头 ,杂交商品猪 12 4头 ;公猪 112头 ,母猪 10 3头 ;体重范围 5～ 4 1kg,平均为 18.6 8± 0 .4 7;日龄 6 3～ 117天 ,平均为 85 .2 4± 0 .78。动物随机分为两组 ,第 1组动物数量为总体数量的 2 / 3,共 14 6头 ,为模型组 ,用于建立群体药动学模型 ;第 2组动物数量为总体动物数量的 1/ 3,共 6 9头 ,为验证组。给药前测定每头猪血清生化指标。试验猪颈部肌肉注射 30 %氟苯尼考注射液 ,剂量为 2 0 mg· kg- 1体重。给药前采一次空白血浆及血清 (测定血清生化指标 ) ,给药后随机采样 ,每只猪采样 2～ 4次 ,就整个群体而言使采样时间均匀分布于药物的吸收相、分布相和消除相内 ,采样时间为给药后 0 .183～ 4 8.36 7h,以高效液相色谱法测定血浆药物浓度 ,应用 NONMEM程序处理所收集的数据 ,包括药时数据、猪只的体重、日龄、性别、种属及血清生化指标、对研究组数据拟合发现最佳药动学模型为一级吸收一室模型 ,药动学参数随机效应及自身变异的最佳模型均为对数加法模型。体重对机体清除率、表观分布容积有显著影响 ,机体清除率、表观分布容积随体重的增加而增加 ,基本呈线性关系。种属对吸收速率常数有显著影响。把研究组得到的群体药动学参数值应用     

Pharmacokinetics of florfenicol after intravenous and intramuscular administration in New Zealand White rabbits

The pharmacokinetic disposition and bioavailability of florfenicol (FF) were determined after single intravenous (i.v.) and intramuscular (i.m.) administrations of 25 mg/kg b.w. to ten healthy New Zealand White rabbits. Plasma FF concentrations were determined by high-performance liquid chromatography (HPLC). The plasma pharmacokinetic values for FF were best described by a one-compartment open model. The elimination half-life (t_1/2β) was different (p < 0.05) however, the area under curve (AUC) was similar (p > 0.05) after i.v. and i.m. administrations. FF was rapidly eliminated (t_1/2β 1.49 ± 0.23 h), slowly absorbed and high (F, 88.75 ± 0.22%) after i.m. injection. In addition, FF was widely distributed to the body tissues (V_ss 0.98 ± 0.05 L/kg) after i.v. injection. In this study the time that plasma concentration exceeded the concentration of 2 μg/mL was approximately 6 h. For bacteria with MIC of 2 μg/mL, frequent administration at this dose would be needed to maintain the concentration above the MIC. However, it is possible that rabbit pathogens may have MIC values less than 2 μg/mL which would allow for less frequent administration. Further studies are necessary to identify the range of MIC values for rabbit pathogens and to identify the most appropriate PK-PD parameter needed to predict an effective dose.     

Comparison of plasma pharmacokinetics and bioavailability of ceftiofur sodium and ceftiofur hydrochloride in pigs after a single intramuscular injection

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. Two studies were designed to compare the intramuscular bioavailability of the current sodium salt and the new hydrochloride salt in pigs at doses of either 3 mg or 5 mg ceftiofur equivalents (CE)/kg body weight. Twenty-six healthy young pigs were selected for these two-period, two-treatment crossover studies, 12 for the 3 mg/kg study and 14 for the 5 mg/kg study. Each animal received one intramuscular (i.m.) injection of ceftiofur sodium and one i.m. injection of ceftiofur hydrochloride with a 14-day washout period between the two treatments. Blood samples were collected serially for up to 96 h postinjection. Plasma samples were then analysed using a validated assay that measures ceftiofur and all desfuroylceftiofur-related metabolites by high-performance liquid chromatography. In the 3 mg/kg dosage study, average maximum plasma concentration (C(max)) after administration of ceftiofur sodium was 15.8+/-3.40 microg/mL at 0.4-4 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 11.8+/-1.67 microg/mL at 1-4 h after injection. Concentrations of ceftiofur and metabolites 72 h after the injection were 0.392+/-0.162 microg/mL for ceftiofur hydrochloride and 0.270+/-0.118 microg/mL for ceftiofur sodium. The mean area under the curve (AUC), from time 0 to the limit of quantitation (AUC(O-LOQ)) after ceftiofur hydrochloride administration, was 216+/-28.0 microg x h/mL, compared to 169+/-45.4 microg x h/mL after ceftiofur sodium administration. The calculated time during which plasma concentrations remained above 0.02 microg/mL (t(>0.2)) was 85.3+/-10.6 h for ceftiofur sodium and 77.2+/-10.7 h for ceftiofur hydrochloride. In the 5 mg/kg dosage study, C(max) after administration of ceftiofur sodium was 28.3+/-4.45 microg/mL at 0.33-2 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 29.7+/-6.72 microg/mL at 0.66-2 h after injection. Concentrations of ceftiofur and metabolites 96 h after the injection were 0.274+/-0.0550 microg/mL for ceftiofur hydrochloride and 0.224+/-0.0350 microg/mL for ceftiofur sodium. The mean AUC(O-LOQ) after ceftiofur hydrochloride administration was 382+/-89.8 microg x h/mL compared to 302+/-54.4 microg x h/mL after ceftiofur sodium administration. The t(>0.2) was 78.9+/-9.65 h for ceftiofur sodium and 94.2+/-8.64 h for ceftiofur hydrochloride. Based on the similarity of the pharmacokinetic parameters of the sodium and hydrochloride formulations of ceftiofur, similar therapeutic efficacy can be inferred for the two products.     

Comparison of plasma pharmacokinetics and bioequivalence of ceftiofur sodium in cattle after a single intramuscular or subcutaneous injection

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. This study was designed to compare the bioequivalence of the sodium salt in cattle after a single intramuscular (i.m.) or subcutaneous dose (s.c.) of 2.2 mg ceftiofur equivalents/kg body weight. The criteria used to evaluate bioequivalence were (1) the area under the curve from time of injection to the limit of quantitation (LOQ) of the assay (AUC0-LOQ), and (2) time concentrations remained above 0.2 microg/mL (t>0.2). Twelve crossbred beef cattle were enrolled in a three-period, two-treatment crossover trial, with a minimum 2-week washout period between doses of 2.2 mg ceftiofur equivalents/kg. Blood samples were collected serially for up to 72 h post-injection. Plasma samples were then analyzed using a validated assay that measures ceftiofur, and all desfuroylceftiofur-related metabolites, by high-performance liquid chromatography (HPLC) as the stable derivative, desfuroylceftiofur acetamide. A maximum plasma concentration (Cmax) of 13.9+/-3.55 microg/mL was observed from 0. 67-2.0 h after i.m. administration, whereas a Cmax of 13.6+/-3.85 microg/mL was observed from 0.67-3.0 h after s.c. administration. The AUC0-LOQ was 108+/-35.0 microg. h/mL after i.m. dosing, compared with 105+/-29.8 microg. h/mL after s.c. dosing. The pre-established criterion for equivalence of the AUC0-LOQ for the i.m. and s.c. routes of administration was satisfied. The t>0.2 was 49.2+/-8.55 h after i.m. administration, compared with 47.0+/-9.40 h after s.c. administration. The pre-established criterion for equivalence of the t>0.2 for i.m. and s.c. administration was satisfied. The equivalence of AUC0-LOQ and t>0.2 for i.m. and s.c. administration of 2.2 mg ceftiofur equivalents (CE)/kg doses of ceftiofur sodium suggest similar therapeutic efficacy and systemic safety for the two routes of administration.     

Non-linear pharmacokinetics of ofloxacin after a single intravenous bolus dose in pigs

The pharmacokinetics of ofloxacin (OFLX) was investigated after intravenous administration of 3, 10 and 30 mg/kg of body weight in pigs. Plasma OFLX concentration-time course collected from the highest dosage showed a convex decline, indicating a capacity-limited process in drug elimination (Michaelis-Menten elimination). Dose-normalized area under curve (AUC/Dose) and mean resident time (MRT) were dose-dependent, indicating a classical pattern of non-linear elimination pharmacokinetics. Based on simultaneous curve fitting from three doses, non-linear pharmacokinetic parameters were as follows: 0.87 mg/h/kg for maximum velocity, 2.20 microg/mL in Michaelis-Menten constant and 2.06 L/kg for apparent volume of distribution. Based on a model-independent analysis, the apparent volume of distribution at steady-state (Vdss) was dose-independent whereas total body clearance (CLtot) was dose-dependent, mainly contributed by renal clearance (CLr) with the regression line of CLtot=1.14xCLr+0.09 (r=0.92). The intercept of the regression line indicates non-renal clearance (CLnr), corresponding to the value of observed CLnr without dose-dependency. Because of a higher CLr compared with glomerular filtration rate (GFR) in spite of drug reabsorption, the CLr must contain the renal active tubular secretion. With increasing dosage, the level of saturation of tubular secretion of OFLX decreased the CLr, resulting in the decrease in CLtot. The plasma protein binding to OFLX was dose-independent: mean free fraction (fp)=0.73, with probably no influential effect on OFLX disposition. In conclusion, the degree of saturation in the renal active tubular secretion of OFLX could be a major causal factor in the alteration of CLr in an increasing dosage of OFLX. Accordingly, the alteration of CLr could directly induce the non-linear pharmacokinetics of OFLX in pigs, an important consideration in clinical therapeutics.     

Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration

Pharmacokinetics of florfenicol 30% injectable solution was determined in lactating cows after intravenous, intramammary and intramuscular administration. Serum concentration-time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Florfenicol half-life was 176 min, mean residence time 129 min, volume of distribution at steady-state 0.35 L/kg, and total body clearance 2.7 mL/min·kg after intravenous administration at 20 mg/kg. The absorption after intramuscular administration appeared slow and the kinetic parameters and the serum concentration vs. time curve were characteristic of absorption rate-dependent elimination. The absorption after intramammary administration of florfenicol at 20 mg/kg was good (53.9%) and resulted in serum concentrations with apparent clinical significance. The intramammary administration resulted in serum florfenicol concentrations that were significantly higher than the respective serum concentrations following Intravenous administration 4 h after administration and thereafter. Florfenicol absorption was faster from the mammary gland than from the muscle. The maximum serum concentrations ( C _max) were 6.9 μg/mL at 360 min after intramammary administration and 2.3 μg/mL at 180 min after intramuscular administration. The bioavailability of florfenicol was 54% and 38% after intramammary and intramuscular administration, respectively. The C _max in milk was 5.4 μg/mL at 180 min after intravenous and 1.6 μg/mL at 600 min after intramuscular administration.     

Duration of nonresponse to noxious stimulation after intramuscular administration of butorphanol, medetomidine, or a butorphanol-medetomidine combination during isoflurane administration in dogs

OBJECTIVE: To assess duration of actions of butorphanol, medetomidine, and a butorphanol-medetomidine combination in dogs given subanesthetic doses of isoflurane (ISO). ANIMALS: 6 healthy dogs. PROCEDURE: Minimum alveolar concentration (MAC) values for ISO were determined. for each dog. Subsequently, 4 treatments were administered to each dog (saline [0.9% NaCl] solution, butorphanol [0.2 mg/kg of body weight], medetomidine [5.0 microg/kg], and a combination of butorphanol [0.2 mg/kg] and medetomidine [5.0 microg/kg]). All treatments were administered IM to dogs concurrent with isoflurane; treatment order was determined, using a randomized crossover design. Treatments were given at 7-day intervals. After mask induction with ISO and instrumentation with a rectal temperature probe, end-tidal CO2 and anesthetic gas concentrations were analyzed. End-tidal ISO concentration was reduced to 90% MAC for each dog. A tail clamp was applied 15 minutes later. After a positive response, 1 of the treatments was administered. Response to application of the tail clamp was assessed at 15-minute intervals until a positive response again was detected. RESULTS: Duration of nonresponse after administration of saline solution, butorphanol, medetomidine, and butorphanol-medetomidine (mean +/- SD) was 0.0+/-0.0, 1.5+/-1.5, 2.63+/-0.49, and 5.58+/-2.28 hours, respectively. Medetomidine effects were evident significantly longer than those for saline solution, whereas effects for butorphanol-medetomidine were evident significantly longer than for each agent administered alone. CONCLUSION AND CLINICAL RELEVANCE: During ISO-induced anesthesia, administration of medetomidine, but not butorphanol, provides longer and more consistent analgesia than does saline solution, and the combination of butorphanol-medetomidine appears superior to the use of medetomidine or butorphanol alone.     

Pharmacokinetics of a florfenicol-tylosin combination after intravenous and intramuscular administration to beagle dogs

A pharmacokinetic study of a commercial florfenicol-tylosin (2:1) combination product was conducted in six beagle dogs after intravenous (IV) and intramuscular (IM) administration at doses of 10 mg/kg (florfenicol) and 5 mg/kg (tylosin). Serum drug concentrations were determined by a validated high performance liquid chromatography (HPLC) using UV detection. A rapid and nearly complete absorption of both drugs with a mean IM bioavailability of 103.9% (florfenicol) and 92.6% (tylosin), prolonged elimination half-life, and high tissue penetration with steady state volume of distribution of 2.63 l/kg (florfenicol) and 1.98 l/kg (tylosin) were observed. Additional studies, including pharmacodynamic and toxicological evaluation are required before recommendations can be made regarding the clinical application of the product in dogs.     

Tissue concentrations and pharmacokinetics of florfenicol in male veal calves given repeated doses

The pharmacokinetic disposition of florfenicol was studied in male veal calves given 11 mg of florfenicol/kg of body weight, IV and 11 mg of florfenicol/kg PO every 12 hours for 7 doses. After florfenicol administration IV, the median elimination half-life was 222.8 minutes, whereas the median half-life of the distribution phase was 7.94 minutes. Median body clearance and apparent volume of distribution were 2.87 ml/kg/min and 0.907 L/kg, respectively. After florfenicol administration, PO, there was a wide variation in the calculated half-life, which was attributed to variation in the rate of florfenicol absorption. The half-life was 167.4 to 534.9 minutes after the first oral dose and 190 to 808.8 minutes after the seventh dose. The median bioavailability after the first oral dose was 0.8888. Peak and trough concentrations of florfenicol were increased after subsequent doses were administered, compared with those after the first oral dose. The percentage of protein binding in serum from one adult cow was 22% to 26%. Florfenicol concentrations in tissues and body fluids of male veal calves were studied after the seventh dose of 11 mg of florfenicol/kg. High concentrations of florfenicol were measured in the urine, kidney, and bile. Low concentrations were measured in the brain, CSF, and aqueous humor. Concentrations in all other tissues and fluids studied were similar to the concurrent serum concentration.     

Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and intramuscular administration to horses

The pharmacokinetic properties of norfloxacin-glycine acetate (NFLXGA) were determined in six horses following a single intravenous (i.v.) and intramuscular (i.m.) dose of 4 mgkg(-1) body weight. Following i.v. and i.m. administration, the plasma drug concentrations were best fitted by an open two-compartment model with a rapid distribution phase. After i.v. NFLXGA administration, the distribution (t(1/2alpha)) and elimination half-life (t(1/2beta)) were 0.42 (0.05) and 5.44 (1.36)h. The volume of distribution of NFLXGA at steady state (Vd(ss)) was 2.19 (0.53) Lkg(-1). After NFLXGA i.m. administration, the maximal absorption concentration (C(max)) was 0.44 (0.04) microgml(-1) at 0.86 (0.15)h (T(max)). The mean absorption (t(1/2ka)) and elimination half-life (t(1/2beta)) of NFLXGA were 0.27 (0.07) and 9.47 (2.24)h, respectively. The mean systemic bioavailability (F) following i.m. administration was 55 (12)%. The optimal dosage for each administration route was calculated from the pharmacokinetic data on the basis of the area under the inhibitory plasma concentration-time curve (AUIC) every 24h and was found to be 13.36 and 7.35 mgkg(-1) for i.m. and i.v. administration, respectively.     

Pharmacokinetics of marbofloxacin in mature horses after single intravenous and intramuscular administration

The pharmacokinetic behaviour of marbofloxacin, a new fluoroquinolone antimicrobial agent developed exclusively for veterinary use, was studied in mature horses (n = 5) after single-dose i.v. and i.m. administrations of 2 mg/kg bwt. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and data obtained were subjected to compartmental and noncompartmental kinetic analysis. This compound presents a relatively high volume of distribution (V(SS) = 1.17 +/- 0.18 l/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.19 +/- 0.042 l/kgh, which is related to a long elimination half-life (t(1/2beta) = 4.74 +/- 0.8 h and 5.47 +/- 1.33 h i.v. and i.m. respectively). Marbofloxacin was rapidly absorbed after i.m. administration (MAT = 33.8 +/- 14.2 min) and presented high bioavailability (F = 87.9 +/- 6.0%). Pharmacokinetic parameters are not significantly different between both routes of administration (P>0.05). After marbofloxacin i.m. administration, no adverse reactions at the site of injection were observed. Serum CK activity levels 12 h after administration increased over 8-fold (range 3-15) compared with pre-injection levels, but this activity decreased to 3-fold during the 24 h follow-up period. Based on the value of surrogate markers to predict clinical success, Cmax/MIC ratio or AUC/MIC ratio, single daily marbofloxacin dose of 2 mg/kg bwt may not be effective in treating infections in horses caused by pathogens with an MIC > or = 0.25 microg/ml. However, if we use a classical antimicrobial efficacy criteria, marbofloxacin can reach a high plasma peak concentration and maintain concentrations higher than MICs determined for marbofloxacin against most gram-negative veterinary pathogens throughout the administration period. Taking into account the fact that fluoroquinolones are considered to have a concentration-dependent effect and a long postantibiotic effect against gram-negative bacteria, a dose of 2 mg/kg bwt every 24 h could be adequate for marbofloxacin in horses.     

Terbinafine pharmacokinetics after single dose oral administration in the dog

Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30–35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high‐performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions^® computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 μg·h/mL (range 5–27), maximal plasma concentration (C_max) was 3.5 μg/mL (range 3–4.9 μg/mL) and time to C_max (T_max) was 3.6 h (range 2–6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17–18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5–11 h. The AUC/MIC values ranged from 9 to 13 μg h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs.     

Pharmacokinetics of florfenicol in loggerhead sea turtles (Caretta caretta) after single intravenous and intramuscular injections.

The pharmocodynamics of single injections of florfenicol in yearling loggerhead sea turtles (Caretta caretta) were determined. Eight juvenile loggerhead sea turtles weighing 1.25 (+/- 0.18) kg were divided into two groups. Four animals received 30 mg/kg of florfenicol i.v., and four received the same dose i.m. Plasma florfenicol concentrations were analyzed by reverse-phase high performance liquid chromatography. After the i.v. dose, there was a biphasic decline in plasma florfenicol concentration. The initial steep phase from 3 min to 1 hr had a half-life of 3 min, and there was a longer slow phase of elimination, with a half-life that ranged from 2 to 7.8 hr among turtles. The volume of distribution varied greatly and ranged from 10.46 to -60 L/kg. Clearance after the i.v. dose was 3.6-6.3 L/kg/hr. After the i.m. injection, there was a peak within 30 min of 1.4-5.6 microg/ml, and florfenicol was thereafter eliminated with a half-life of 3.2-4.3 hr. With either route, florfenicol plasma concentrations were below the minimum inhibitory concentrations for sensitive bacteria within 1 hr. Florfenicol does not appear to be a practical antibiotic in sea turtles when administered at these doses.     

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC(90) 0.125 microg/mL) were lower than those of cefoperazone (MIC(90) 0.5 micro/mL) although the latter was more effective against Escherichia coli strains (MIC(90) 2.0 microg/mL vs. 4.0 microg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase (t((1/2)lambda2) 84.0+/-21.3 min for cefoperazone and 81.4+/-9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1+/-13.5% and 35.9+/-5.4 microg/mL) were significantly higher than cefoperazone (41.4+/-7.1% and 24.5+/-3.0 micog/mL), but not the serum half-lives (t(1/2el) 134.3+/-12.6 min for cefoperazone and 145.4+/-12.3 min for cefamandole). The time above MIC(90) indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections (T>MIC for S. intermedius 23.8+/-0.3 and for Staphylococcus aureus 21.6+/-0.6h).     

Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and oral administration in pigs

The pharmacokinetics and dosage regimen of norfloxacin-glycine acetate (NFLXGA) was investigated in pigs after a single intravenous (i.v.) or oral (p.o.) administration at a dosage of 7.2 mg/kg body weight. After both i.v. and p.o. administration, plasma drug concentrations were best fitted to an open two-compartment model with a rapid distribution phase. After i.v. administration of NFLXGA, the distribution (t_1/2α) and elimination half-life (t_1/2β) were 0.36 ± 0.07 h and 7.42 ± 3.55 h, respectively. The volume of distribution of NFLXGA at steady state (Vd_ss) was 4.66 ± 1.39 l/kg. After p.o. administration of NFLXGA, the maximal absorption concentration (C_max) was 0.43 ± 0.06 µg/ml at 1.36 ± 0.39 h (T_max). The mean absorption (t_1/2ka) and elimination half-life (t_1/2β) of NFLXGA were 0.78 ± 0.27 h and 7.13 ± 1.41 h, respectively. The mean systemic bioavailability (F) after p.o. administration was 31.10 ± 15.16%. We suggest that the optimal dosage calculated from the pharmacokinetic parameters is 5.01 mg/kg per day i.v. or 16.12 mg/kg per day p.o.     

A comparison of two intramuscular doses of xylazine–ketamine combination and tolazoline reversal in llamas

The anesthetic and cardiorespiratory effects of a low dose (LD, 0.4 mg kg^?1 xylazine and 4 mg kg^?1 ketamine) and a high dose (HD, 0.8 mg kg^?1 xylazine and 8 mg kg^?1 ketamine) of IM xylazine–ketamine combination were compared in a randomized cross‐over study using six castrated male llamas. Three llamas in each dosage group (LDT, HDT) were assigned to receive IM tolazoline (2 mg kg^?1) after 30 minutes of recumbency. All IM injections were given in the semitendinosus or semimembranosus muscles. Pulse, respiratory rate, and indirect arterial blood pressure were recorded every 10 minutes, and hemoglobin oxygen saturation was recorded every 5 minutes during lateral recumbency. Samples for arterial blood gas analysis were collected 5 minutes following recumbency and every 30 minutes thereafter. Base‐to‐apex ECG was monitored continuously. Analgesia was evaluated every 5 minutes by both a 30 minutes skin pinch and a needle prick of the toe. Most llamas breathed room air throughout anesthesia. Two llamas that developed severe hypoxemia (SpO₂ < 75%) received 5 minutes of nasal oxygen insufflation, but were maintained on room air for the rest of the anesthetic period. anova for repeated measures and Tukey's test were used to analyze cardiorespiratory data. Fischer's exact test was used to compare the ability of each to provide >30 minutes of lateral recumbency and analgesia. A p‐value < 0.05 was considered significant. Both dosages provided reasonably rapid induction following injection (LD: 10.8 ± 6.3 minutes; HD: 5.0 ± 1.1 minutes; p = 0.07). Duration of lateral recumbency and analgesia were 34.7 ± 6.7 and 27.3 ± 4.6 minutes, respectively, in the LDT llamas. None of the three remaining LD llamas remained in lateral recumbency for longer than 12 minutes. Duration of lateral recumbency and analgesia were 87.3 ± 18.5 and 67.7 ± 16.0 minutes, respectively, for the HD llamas that did not receive tolazoline. The HDT llamas were recumbent for a significantly shorter time (43.3 ± 0.6 minutes; p = 0.05). The ability to provide >30 minutes of recumbency and analgesia was better in the HD group (6/6) than in the LD group (2/6) (p = 0.03). No differences between dosages were seen in pulse rate, respiratory rate, or arterial pressures. No ECG abnormalities were seen. Transient hypoxemia was seen in the first 10 minutes of lateral recumbency in the HD group by both hemoglobin oxygen saturation (84 ± 9.5%) and by blood gas PaO₂ (44.5 ± 5.8 mm Hg). It was concluded that the HD provided more consistent results than the LD, but induced transient hypoxemia. Tolazoline shortened the recovery time in llamas receiving the HD.