Pharmacokinetics and bioavailability of chloramphenicol in normal and febrile goats

The effect of induced fever on the plasma concentrations and disposition kinetics of chloramphenicol (CHPC) was studied in adult goats. Fever was induced and maintained for 12 h by injecting Escherichia coli endotoxin (0.1 microgram/kg, i.v.) and repeating it at half the dose (0.05 microgram/kg) 8 h later. Pharmacokinetics of CHPC was studied in both normal (n = 6) and febrile (n = 6) animals following intravenous administration of CHPC Na-succinate (25 mg/kg). Intramuscular bioavailability of the drug was also investigated in both normal and febrile animals. Pharmacokinetics of CHPC following intravenous administration could be described by a two-compartment open model in both normal and febrile animals. In normal animals the half-life of CHPC was 73.0 +/- 4.95 min and the volume of distribution was 2.217 +/- 0.24 l/kg. These and other pharmacokinetic parameters did not differ significantly (P less than 0.05) between normal and febrile animals, except for Cop and A. Absorption of CHPC following intramuscular administration was good as indicated by its high bioavailability in both normal (83.34%) and febrile (81.98%) animals. Volume of distribution is usually expected to change when the febrile state is induced. Lack of such an effect in the present study could be due to high individual variation, or to the fact that CHPC already has a relatively large volume of distribution, which is less likely to be altered by a febrile state of short duration.     

Pharmacokinetics of imidocarb in normal dogs and goats

The pharmacokinetics of imidocarb were studied in seven mongrel dogs and eight crossbred goats. An intravenous bolus dose (4 mg/kg) of 12% imidocarb dipropionate solution wasinjected into the cephalic vein in dogs and the jugular vein in goats. The plasma concentration of imidocarb was measured by spectro-photometry. The experimental data were analysed using a two-compartment open model. The apparent volume of the central compartment was significantly higher ( P <0.01) in dogs than in goats. The significantly larger ( P <0.05) apparent specific volume of distribution in goats than in dogs may be attributed to passive diffusion followed by ion trapping of the drug in rumen fluid. Neither the half-life nor body clearance differed significantly between dogs ( t _1/2, 207 ± 45 min; Cl_B , 1.47 ± 0.38 ml/min kg) and goats ( t _1/2, 251 ± 94 min; Cl_B , 1.62 ± 0.50 ml/min kg). While almost 80% of the dose had been eliminated at 8 h in. both species, the high ratio of the imidocarb level in the peripheral-to-central compartment in goats suggests that a prolonged period may be required for complete elimination of the drug.     

Pharmacokinetics and urinary excretion of sulphadimidine in buffalo calves

Pharmacokinetics and urinary excretion of sulphadimidine (SDI) were determined in buffalo calves following single oral administration (150 mg/kg). The plasma levels of free sulphadimidine were above minimum effective therapeutic concentration (> 40 micrograms/ml) between 4 and 12 h and the N4-acetylated form of the drug was in the range of 7.2-19.3%. Kinetic evaluation of plasma levels was performed using a two-compartment open model. The absorption and elimination half-lives of SDI were 3.01 and 11.94 h, respectively. Based on this study, an optimal dosage regimen of sulphadimidine in buffalo calves would be 100 mg/kg, followed by 50 mg/kg at 12 h intervals. Sulphadimidine was mainly excreted in the urine as free amine. The percentage of N4-acetyl sulphadimidine in urine was comparatively higher than in plasma.     

Pharmacokinetics and urinary excretion of sulphadimidine in sheep and goats

Pharmacokinetics and urinary excretion of sulphadimidine were determined in sheep and goats following a single intravenous injection (100 mg/kg). The disposition of the drug was described in terms of exponential expression: C _p= Be ^-βt. Based on total (free and bound) sulphonamide level in plasma, pseudo-distribution equilibrium was rapidly attained and the half-life for elimination was 3.88 ± 0.64 h and 4.00 ± 0.34 h in sheep and goats, respectively. Body clearance, which is the sum of all clearance processes was 88 ± 19 and 55 ± 4 ml/kg/h in sheep and goats. Based on this study a satisfactory intravenous dosage regimen might consist of 100 and 60 mg sulphadimidine/kg body wt for sheep and goats and should be repeated at 12 h intervals. The influence of disease conditions on predicted plasma levels remain to be verified experimentally. Three-quarters of an intravenously injected dose of sulphadimidine was excreted in the urine of sheep and goats within 24 h of administration. The drug was mainly excreted as free amine while acetylated drug constituted 7 and 8% of total drug content in the urine of sheep and goats, respectively.     

Pharmacokinetics of gentamicin following single dose intravenous administration in normal and febrile goats

A pharmacokinetic study of gentamicin (5 mg/kg intravenous (i.v.)) was conducted first in cinically healthy female goats and then in the same goats after induction of fever by Escherichia coli endotoxin (0.2 μg/kg i.v.). Rectal temperature increased 1 to 1.5°C in febrile goats. Differences in the blood serum concentrations of gentamicin were not observed at any time between febrile and normal goats. The disposition kinetics of gentamicin were described by a biex-ponential expression C_P= Ae^-αt+ Be^-β. Median values for the half-lives of gentamicin were 103.6 min in normal and 136.0 min in febrile goats. The apparent volume of distribution (V_d) was 263.3 ml/kg in the febrile goats which was not different from that in the normal goats (240.6 ml/kg). The volume of the central compartment (V_c) was almost identical in normal and febrile goats. The body clearance (Cl_β) was observed to be 1.7 and 1.6 ml/min-kg in normal and febrile goats, respectively. Dosage regimens for gentamicin were calculated on the basis of median kinetic data.     

Pharmacokinetics of single-dose oral pregabalin administration in normal dogs

ObjectiveTo describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose.Study designProspective experiment.AnimalsSix adult Labrador/Greyhound dogs (four females and two males) aged 2.6 (2.6–5.6) years old (median and range) weighing 33.4 (26.8–42.1) kg.MethodsAfter jugular vein catheterization, the dogs received a single oral dose of pregabalin (～4 mg kg^?1). Blood samples were collected at: 0 (before drug administration), 15 and 30 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours after drug administration. Plasma pregabalin concentration was measured by HPLC. Noncompartmental analysis was used to estimate pharmacokinetic variables.ResultsNo adverse effects were observed. The median (range) pharmacokinetic parameters were: Area under the curve from time 0 to 36 hours = 81.8 (56.5–92.1) μg hour mL^?1; absorption half-life = 0.38 (0.25–1.11) hours; elimination half-life = 6.90 (6.21–7.40) hours; time over 2.8 μg mL^?1 (the presumed minimal effective concentration) = 11.11 (6.97–14.47) hours; maximal plasma concentration (C_max) = 7.15 (4.6–7.9) μg mL^?1; time for C_max to occur = 1.5 (1.0–4.0) hours. Assuming an 8-hour dosing interval, predicted minimal, average, and maximal steady state plasma concentrations were 6.5 (4.8–8.1), 8.8 (7.3–10.9), and 13.0 (8.8–15.2) μg mL^?1. The corresponding values assuming a 12-hour interval were 3.8 (2.4–4.8), 6.8 (4.9–7.9), and 10.1 (6.6–11.6) μg mL^?1.Conclusions and clinical relevancePregabalin 4 mg kg^?1 PO produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to suggest that a twice daily dosing regime would be adequate. Further study of the drug's safety and efficacy for the treatment of neuropathic pain and seizures in dogs is warranted.     

Pharmacokinetics of single-dose intravenous levetiracetam administration in normal dogs

Objective: To determine plasma pharmacokinetics of levetiracetam after a single intravenous dose (60 mg/kg) in normal dogs using a high‐performance liquid chromatography assay validated for canine plasma. Design: Pharmacokinetic study. Setting: A university‐based canine research facility. Animals: Six healthy adult dogs. Interventions: Intravenous drug administration, multiple blood sample procurement. Measurements and main results: There were no obvious adverse effects associated with the intravenous (IV) bolus administration of levetiracetam in any of the dogs. Plasma levetiracetam concentrations remained above or within the reported therapeutic range for humans (5–45 μg/mL) for all dogs, for all time periods evaluated. Mean and median (in parentheses) values for pharmacokinetic parameters included the following: maximum plasma concentration, 254 μg/mL (254 μg/mL); half‐life, 4.0 hours (4.0 hours); volume of distribution at steady state, 0.48 L/kg (0.48 L/kg); clearance, 1.4 mL/kg/min (1.5 mL/kg/min); and median residence time, 6.0 hours (6.0 hours). Conclusions: In normal dogs, a 60 mg/kg IV bolus dose of levetiracetam is well tolerated and achieves plasma drug concentrations within or above the therapeutic range reported for humans for at least 8 hours after administration. Based on the favorable pharmacokinetics and tolerability demonstrated for IV levetiracetam in this study, in addition to previously demonstrated efficacy of oral levetiracetam, IV levetiracetam may be a useful treatment option for emergency management of canine seizure activity.     

Pharmacokinetics and urinary excretion of sulphadimidine in sheep during summer and winter

Pharmacokinetics and urinary excretion of sulphadimidine were investigated in sheep during summer and winter seasons. Average minimum and maximum environmental temperature in the summer ranged from 22.6 to 40.2 degrees C and in winter from 4.5 to 21.1 degrees C. The determination of plasma volume, plasma protein and packed cell volume during summer and winter revealed a significant decrease in plasma volume and a significant increase in plasma protein in the summer indicative of haemoconcentration. Packed cell volume did not differ significantly between the seasons. The pharmacokinetics of sulphadimidine were determined following a single intravenous injection (100 mg/kg) in summer and winter. Zero time plasma concentration of the drug was higher during summer than in winter. The elimination half-life of the drug was similar in summer and winter, but the apparent volume of distribution was lower in summer. Likewise, total body clearance was significantly lower in summer. Based on these studies a satisfactory intravenous dosage regimen might consist of 86 and 100 mg/kg for priming and 78 and 88 mg/kg as maintenance doses during summer and winter, respectively, the doses being repeated at 12 hour intervals. Twenty four hours after sulphadimidine administration 90 and 73 per cent of the dose was excreted in urine during summer and winter, respectively. The drug was excreted mainly as free amine.     

Pharmacokinetics of hexobarbital, sulphadimidine and chloramphencoliin neonatal and young pigs.

Half-life and apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol were investigated in newborn, 1, 3, 5 and 8 weeks old pigs. Hexobarbital sleeping time and plasma concentration of hexobarbital at recovery were measured in the same age groups. The half-life of hexobarbital and chloramphenicol was long in newborn pigs but decreased fast during the first week after birth. From 1 to 8 weeks after birth the decrease was less pronounced. The half-life of sulphadimidine increased during the first 3 weeks of life, but in 1 and 3 weeks old pigs the amount of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection was higher than in the newborn pigs.The apparent specific volume of distribution of hexobarbital, sulphadimidine and chloramphenicol was changed in different ways from birth to 8 weeks of age.The hexobarbital sleeping time was very long in the newborn pigs and decreased until 3 weeks of age. The concentration of hexobarbital in plasma at recovery was unchanged from birth to 8 weeks of age.The concentration of chloramphenicol metabolites in plasma 100 min. after the injection increased very fast during the 8 weeks of observation. The concentration of N⁴-acetylated sulphadimidine in plasma at 200 min. after the injection increased from birth to 1 week of age, then it decreased.The data are stressing that the neonatal pig is a convenient model for pharmacokinetic testing of drugs used as pharmacotherapeutics in neonatal life.     

Pharmacokinetics and metabolism of sulphadimidine in kids at 12 and 18 weeks of age

The pharmacokinetics and metabolism of sulphadimidine (SDM) following intravenous administration of 100 mg/kg were studied in seven dwarf preruminant kids at 12 weeks of age, and again at the ruminant stage, when the animals were 18 weeks old. The persistence of SDM in 18-week-old kids was prolonged in comparison to the 12-week-old animals: a lower total body clearance and a prolonged elimination of SDM were obtained in the older animals. The renal clearance values of SDM and its metabolites were the same at both ages. The decrease of SDM clearance is related to the significant reduction in SDM hydroxylation at the older age. The reduced oxidative hepatic metabolism may result from the sexual maturation of the kids.     

Pharmacokinetics of antipyrine and sulphadimidine (sulfamethazine) in camels, sheep and goats

The pharmacokinetics of antipyrine and sulphadimidine were studied in male camels, sheep and goats. The two drugs were administered concomitantly. Following intravenous injection of antipyrine (25 mg/kg) and sulphadimidine (sulfamethazine) (100 mg/kg), the pharmacokinetics of the two drugs were adequately described by a one-compartment model. Antipyrine half-life in goats (2.58 h) was shorter than that in sheep (4.04 h) and camels (18.78 h). The plasma clearance was greatest in goats then sheep and then camels. For sulphadimidine, a significantly greater volume of distribution was observed in camels and the greatest plasma clearance and shortest half-life were reported in goats. Sulphadimidine half-life was 2.77 h in goats, 4.72 h in sheep and 7.36 h in camels. The present results suggest that goats have the fastest elimination of these drugs from the circulation, followed by sheep and then camels.     

Pharmacokinetics and distribution of sulphadimidine in plasma,milk and uterine fluid of female buffaloes

The pharmacokinetics of sulphadimidine after a single dose (200 mg/kg i.v.) was studied in five healthy lactating buffaloes. The study revealed that the drug attained its peak concentration of 314.0±13.0, 242.4±3.0 and 100.2±2.5 g/ml at 15 min, 30 min and 12 h in plasma, milk and uterine fluid, respectively. The pharmacokinetic parameters calculated by a 2-compartment open model gave values for t₁, t₁ and vd_area of 2.10±0.36 h, 12.36±0.57 h and 1.23±0.07 L/Kg, respectively. A high vd_area as well as a value of 0.74±0.08 for K₁₂:K₂₁- (tissue Plasma) indicates better penetration of the drug into the different body fluids and tissues, which is further supported by a high concentration obtained in milk and uterine fluid. The therapeutic concentration (50 g/ml) was maintained for around 24 h in plasma and milk and 12 h in uterine fluid. The results suggest that, apart from its use in systemic infections, the drug can be effectively used by the i.v. route in uterine and mammary gland infections. The dosages for maintaining concentration of 50 g/ml, 100 g/ml and 150 g/ml at convenient dosage intervals of 12 and 24 h were also determined.     

Pharmacokinetics of fenbendazole in dogs

Fenbendazole was administered to dogs at a dose rate of 20 mg/kg body weight on a single occasion in gelatin capsules, on 5 consecutive days in feed, and on a single occasion as an alginate suspension. It was also administered at a dose rate of 100 mg/kg body weight on a single occasion in feed. Following single administration of 20 mg/kg fenbendazole mean maximum concentrations (Cmax) of the parent drug and its known active sulphoxide metabolite were 0.42 +/- 0.05 and 0.31 +/- 0.05 microgram/ml, respectively. Mean times until maximum concentrations were achieved (tmax) were 12.67 +/- 4.18 and 15.33 +/- 2.81 h, respectively, and areas under the plasma concentration-time curves (AUC) were 5.83 +/- 0.65 and 4.60 +/- 0.57 microgram.h/ml, respectively. Administration in feed increased the apparent bioavailability and administration for 5 consecutive days provided sustained plasma concentrations, generally greater than 0.2 microgram/ml. Administration as an alginate did not increase bioavailability or extend the persistence in plasma. It did increase the tmax to 16.80 +/- 2.93 and 20.00 +/- 2.53 h for fenbendazole and its sulphoxide metabolite, respectively. Increasing the dose from 20 mg/kg to 100 mg/kg did not substantially increase the Cmax or AUC.     

Pharmacokinetics of imipenem in dogs

OBJECTIVE: To determine the plasma pharmacokinetics of imipenem (5 mg/kg) after single-dose IV, IM, and SC administrations in dogs and assess the ability of plasma samples to inhibit the growth of Escherichia coli in vitro. ANIMALS: 6 adult dogs. PROCEDURE: A 3-way crossover design was used. Plasma concentrations of imipenem were measured after IV, IM, and SC administration by use of high-performance liquid chromatography. An agar well antimicrobial assay was performed with 3 E coli isolates that included a reference strain and 2 multidrug-resistant clinical isolates. RESULTS: Plasma concentrations of imipenem remained above the reported minimum inhibitory concentration for E coli (0.06 to 0.25 microg/mL) for a minimum of 4 hours after IV, IM, and SC injections. Harmonic mean and pseudo-standard deviation half-life of imipenem was 0.80 +/- 0.23, 0.92 +/- 0.33, and 1.54 +/- 1.02 hours after IV, IM, and SC administration, respectively. Maximum plasma concentrations (Cmax) of imipenem after IM and SC administration were 13.2 +/- 4.06 and 8.8 +/- 1.7 mg/L, respectively. Time elapsed from drug administration until Cmax was 0.50 +/- 0.16 hours after IM and 0.83 +/- 0.13 hours after SC injection. Growth of all 3 E coli isolates was inhibited in the agar well antimicrobial assay for 2 hours after imipenem administration by all routes. CONCLUSIONS AND CLINICAL RELEVANCE: Imipenem is rapidly and completely absorbed from intramuscular and subcutaneous tissues and effectively inhibits in vitro growth of certain multidrug-resistant clinical isolates of E coli.     

Pharmacokinetics of kanamycin in dogs

The pharmacokinetics of kanamycin were studied in beagle dogs. A parenteral preparation of kanamycin sulphate (5% aqueous solution), which was given at a dosage level of 10 mg/kg of body weight, was the drug product used. The disposition curve which resulted from the intravenous administration of a single bolus dose of the drug was completely described by the biexponential equation:
C _p= 50e^{-0.1977 t} + 36.3e^{-0.0128 t} where C _p represents concentration of the drug in the serum at time t (in minutes) and the experimental constants are mean values. Pseudo-distribution equilibrium was rapidly attained and the apparent volumes of the central and peripheral compartments of the two-compartment open model were the same ( ca 125 ml/kg). Body clearance (mean ± S.D., n = 6) of kanamycin was 3.21 ±0.72 ml/kg/min. The half-life of the drug was short (58.18 ± 18.43 min) and independent of the route of parenteral (intravenous and intramuscular) administration. Absorption of kanamycin from the intramuscular site was rapid, with a half-time of 9.08 ± 1.10 min. A systemic availability of 89.1 ± 15.8% was obtained. Based on the bioavailability and disposition kinetics a dosage regimen consisting of the intramuscular injection of the dose (10 mg/kg) at 6 h intervals is proposed. An intravenous infusion rate of 48 μg/kgymin is predicted to establish a steady state serum concentration of 15 μg/ml, which is a therapeutic level of the antibiotic for susceptible micro-organisms.     

头孢维星在犬体内的药动学及生物利用度研究

建立了一种头孢维星在犬血浆中的高效液相色谱检测法,并研究了头孢维星在犬体内的药动学特征及生物利用度。选用健康家犬12只,按单剂量(8 mg/kg b.w.)分别静脉注射或皮下注射头孢维星,利用建立的方法对头孢维星在犬血浆中的浓度进行测定,采用Win Nonlin5.2.1程序的非房室模型处理药时数据。结果显示,静脉注射组的主要药动学参数为t1/2β=129.15±35.79 h;MRT=152.56±44.95 h;λz=0.0059±0.0023 h-1;Cl=1.24±0.56 m L/(h·kg);AUC=6942.88±2462.48μg獉h/m L;V=170.20±28.09 m L/kg。皮下注射组的主要药动学参数为t1/2β=136.94±20.96 h;MRT=167.77±28.15 h;Tmax=0.83±0.26 h;Cmax=59.51±7.99μg/m L;λz=0.0052±0.0009 h-1;Cl=1.05±0.21 m L/(h·kg);AUC=7332.58±1118.30μg·h/m L;V=203.81±30.09 m L/kg;F=105.61%。结果表明,头孢维星在家犬体内表现出吸收迅速、消除缓慢、表观分布容积大、生物利用度高等药动学特点。