Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses

ObjectiveTo compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration.Study designRandomized, masked, crossover design.AnimalsA total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg.MethodsHorses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg^⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg^⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (f_R), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant.ResultsThe mean ± SD hydromorphone terminal half-life (t_1/2), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute^⁻1 kg^⁻1 and 1125 ± 309 mL kg^⁻1. The t_1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL^⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02).Conclusions and clinical relevanceIM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration.IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration.     

Pharmacokinetics and pharmacodynamics of butorphanol in llamas after intravenous and intramuscular administration.

OBJECTIVE: To evaluate disposition of butorphanol after i.v. and i.m. administration, effects on physiologic variables, and analgesic efficacy after i.m. administration in llamas. DESIGN: Nonrandomized crossover study. ANIMALS: 6 healthy adult male llamas. PROCEDURE: Butorphanol (0.1 mg/kg [0.045 mg/lb] of body weight) was administered i.m. first and i.v. 1 month later. Blood samples were collected intermittently for 24 hours after administration. Plasma butorphanol versus time curves were subjected to pharmacokinetic analysis. Two months later, butorphanol (0.1 mg/kg) was administered i.m., and physiologic variables and analgesia were assessed. RESULTS: Extrapolated peak plasma concentrations after i.v. and i.m. administration were 94.8 +/- 53.1 and 34.3 +/- 11.6 ng/ml, respectively. Volume of distribution at steady state after i.v. administration was 0.822 +/- 0.329 L/kg per minute and systemic clearance was 0.050 +/- 0.014 L/kg per minute. Slope of the elimination phase was significantly different, and elimination half-life was significantly shorter after i.v. (15.9 +/- 9.1 minutes) versus i.m. (66.8 +/- 13.5 minutes) administration. Bioavailability was 110 +/- 49% after i.m. administration. Heart rate decreased and rectal temperature increased. Somatic analgesia was increased for various periods. Two llamas became transiently sedated, and 2 became transiently excited after butorphanol administration. CONCLUSIONS AND CLINICAL RELEVANCE: Although i.v. administration of butorphanol results in a short half-life that may limit its analgesic usefulness, the elimination half-life of butorphanol administered i.m. is likely to be clinically useful. The relationship among plasma butorphanol concentration, time, and analgesia differed with the somatic analgesia model; clinically useful analgesia may occur at lower plasma concentrations than those reported here.     

Pharmacokinetics of cefuroxime after intravenous,intramuscular, and subcutaneous administration to dogs

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12‐h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (C_max), time‐to‐peak plasma concentration (T_max), and bioavailability for the intramuscular and subcutaneous administration were (mean ± SD) 22.99 ± 7.87 μg/mL, 0.43 ± 0.20 h, and 79.70 ± 14.43% and 15.37 ± 3.07 μg/mL, 0.99 ± 0.10 h, and 77.22 ± 21.41%, respectively. Elimination half‐lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 ± 0.19 h and 1.49 ± 0.21 h; 1.13 ± 0.13 and 1.79 ± 0.24 h; and 1.04 ± 0.23 h and 2.21 ± 0.23 h, respectively. Significant differences were found between routes for K_a, MAT, C_max, T_max, t_½(a), and MRT. T > MIC = 50%, considering a MIC of 1 μg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 μg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.     

The pharmacokinetics of midazolam after intravenous,intramuscular, and rectal administration in healthy dogs

Intravenous benzodiazepines are utilized as first‐line drugs to treat prolonged epileptic seizures in dogs and alternative routes of administration are required when venous access is limited. This study compared the pharmacokinetics of midazolam after intravenous (IV), intramuscular (IM), and rectal (PR) administration. Six healthy dogs were administered 0.2 mg/kg midazolam IV, IM, or PR in a randomized, 3‐way crossover design with a 3‐day washout between study periods. Blood samples were collected at baseline and at predetermined intervals until 480 min after administration. Plasma midazolam concentrations were measured by high‐pressure liquid chromatography with UV detection. Rectal administration resulted in erratic systemic availability with undetectable to low plasma concentrations. Arithmetic mean values ± SD for midazolam peak plasma concentrations were 0.86 ± 0.36 μg/mL (C₀) and 0.20 ± 0.06 μg/mL (C_max), following IV and IM administration, respectively. Time to peak concentration (T_max) after IM administration was 7.8 ± 2.4 min with a bioavailability of 50 ± 16%. Findings suggest that IM midazolam might be useful in treating seizures in dogs when venous access is unavailable, but higher doses may be needed to account for intermediate bioavailability. Rectal administration is likely of limited efficacy for treating seizures in dogs.     

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.     

Pharmacokinetics and effects of alfaxalone after intravenous and intramuscular administration to cats

AIMS: To determine the pharmacokinetics, and anaesthetic and sedative effects of alfaxalone after I/V and I/M administration to cats.

METHODS: Six European shorthair cats, three males and three females, with a mean weight of 4.21 (SD 0.53) kg and aged 3.8 (SD 0.9) years were enrolled in this crossover, two–treatment, two-period study. Alfaxalone at a dose of 5?mg/kg was administered either I/V or I/M. Blood samples were collected between 2–480 minutes after drug administration and analysed for concentrations of alfaxalone by HPLC. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation scores were evaluated between 5–120 minutes after drug administration using a numerical rating scale (from 0–18). Intervals from drug administration to sit, sternal and lateral recumbency during the induction phase, and to head-lift, sternal recumbency and standing position during recovery were recorded.

RESULTS: The mean half-life and mean residence time of alfaxalone were longer after I/M (1.28 (SD 0.21) and 2.09 (SD 0.36) hours, respectively) than after I/V (0.49 (SD 0.07) and 0.66 (SD 0.16) hours, respectively) administration (p<0.05). Bioavailability after I/M injection of alfaxalone was 94.7 (SD 19.8)%. The mean intervals to sternal and lateral recumbency were longer in the I/M (3.73 (SD 1.99) and 6.12 (SD 0.90) minutes, respectively) compared to I/V (0 minutes for all animals) treated cats (p<0.01). Sedation scores indicative of general anaesthesia (scores >15) were recorded from 5–15 minutes after I/V administration and deep sedation (scores 11–15) at 20 and 30 minutes. Deep sedation was observed from 10–45 minutes after I/M administration. One cat from each group showed hyperkinesia during recovery, and the remainder had an uneventful recovery.

CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone administered I/V in cats provides rapid and smooth induction of anaesthesia. After I/M administration, a longer exposure to the drug and an extended half life were obtained compared to I/V administration. Therefore I/M administration of alfaxalone could be a reliable, suitable and easy route in cats, taking into account that alfaxalone has a slower onset of sedation than when given I/V and achieves deep sedation rather than general anaesthesia.     

Pharmacokinetics of danofloxacin in horses after intravenous, intramuscular and intragastric administration

REASONS FOR PERFORMING STUDY: Danofloxacin is a fluoroquinolone developed for veterinary medicine showing an excellent activity. However, danofloxacin pharmacokinetics profile have not been studied in horses previously. OBJECTIVE: To study the pharmacokinetics following i.v., i.m. and intragastric (i.g.) administration of 1.25 mg/kg bwt danofloxacin to 6 healthy horses. METHODS: A cross-over design was used in 3 phases (2 x 2 x 2), with 2 washout periods of 15 days (n = 6). Danofloxacin (18%) was administered by i.v. and i.m. routes at single doses of 1.25 mg/kg bwt. For i.g. administration an oral solution was prepared and administered via nasogastric tube. Danofloxacin concentrations were determined by HPLC assay with fluorescence detection. Tolerability at the the site of i.m. injection was monitored by creatine kinase (CK) activity. RESULTS: Danofloxacin plasma concentration vs. time data after i.v. and i.g. administration could best be described by a 2-compartment open model. The disposition of i.m. administered danofloxacin was best described by a one-compartment model. The terminal half-lives for i.v., i.m. and i.g. routes were 6.31, 5.36 and 4.74 h, respectively. Clearance value after i.v. dosing was 0.34 l/kg bwt/h. After i.m. administration, absolute bioavailability was mean +/- s.d. 88.48 +/- 11.10% and Cmax was 0.35 +/- 0.05 mg/l. After i.g. administration, absolute bioavailability was 22.36 +/- 6.84% and Cmax 0.21 +/- 0.07 mg/l. CK activity following i.m. dosing increased 3-fold over pre-injection levels 12 h after dosing and subsequently approached (but did not reach) normal values at 72 h post dose. CONCLUSIONS: Systemic danofloxacin exposure achieved in horses following i.m. administration was consistent with the predicted blood levels needed for a positive therapeutic outcome for many equine infections. Conversely, danofloxacin utility by the i.g. route was limited by low bioavailability. Tolerability associated with i.m. administration was high. POTENTIAL RELEVANCE: Pharmacokinetics, blood levels and good tolerability of i.v. and i.m. administration of danofloxacin in horses indicates that it is likely to be effective for treating sensitive bacterial infections.     

Pharmacokinetics of chloramphenicol in sheep after intravenous, intramuscular and subcutaneous administration

The pharmacokinetics of chloramphenicol were studied in sheep after 3 single intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations (30 mg/kg). The two extravascular routes were studied during a crossover trial for a bioequivalence test. After IV and SC administrations, the plasma-concentration time graphs were characteristic of a two-compartment model, and after IM administration it was characteristic of a monocompartment model. The two routes of absorption were not bioequivalent. Using the kinetic values, multidose regimens to maintain the therapeutic chloramphenicol blood level (5 micrograms/ml) were proposed: 60 mg/kg every 12 hours for 72 hours for the IM administration and 45 mg/kg administered subcutaneously according to the same regimen. A study of the chloramphenicol residues in tissues was carried out. Chloramphenicol residues remained at the injection site, and 400 hours would be necessary to obtain the level of 10 micrograms/kg. Determination of the creatinine phosphokinase serum values showed that the subcutaneous route induced less damage to muscle than the intramuscular route.     

Pharmacokinetics after intravenous, intramuscular and subcutaneous administration of difloxacin in sheep

The disposition kinetics of difloxacin, a fluoroquinolone antibiotic, after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration were determined in sheep at a single dose of 5mg/kg. The concentration-time data were analysed by compartmental (after IV dose) and non-compartmental pharmacokinetics method (after IV, IM and SC administration). Plasma concentrations of difloxacin were determined by high performance liquid chromatography with fluorescence detection. Steady-state volume of distribution (V(ss)) and clearance (Cl) of difloxacin after IV administration were 1.68+/-0.21L/kg and 0.21+/-0.03L/hkg, respectively. Following IM and SC administration difloxacin achieved maximum plasma concentration of 1.89+/-0.55 and 1.39+/-0.14mg/L at 2.42+/-1.28 and 5.33+/-1.03h, respectively. The absolute bioavailabilities after IM and SC routes were 99.92+/-26.50 and 82.35+/-25.65%, respectively. Based on these kinetic parameters, difloxacin is likely to be effective in sheep.     

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.     

Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets

The pharmacokinetics and bioavailability of butafosfan in piglets were investigated following intravenous and intramuscular administration at a single dose of 10 mg/kg body weight. Plasma concentration–time data and relevant parameters were best described by noncompartmental analysis after intravenous and intramuscular injection. The data were analyzed through WinNolin 6.3 software. After intravenous administration, the mean pharmacokinetic parameters were determined as T_1/2λz of 3.30 h, Cl of 0.16 L kg/h, AUC of 64.49 ± 15.07 μg h/mL, V_ss of 0.81 ± 0.44/kg, and MRT of 1.51 ± 0.27 h. Following intramuscular administration, the C_max (28.11 μg/mL) was achieved at T_max (0.31 h) with an absolute availability of 74.69%. Other major parameters including AUC and MRT were 48.29 ± 21.67 μg h/mL and 1.74 ± 0.29 h, respectively.     

Pharmacokinetics after intravenous, intramuscular and subcutaneous administration of moxifloxacin in sheep

The disposition kinetics of moxifloxacin, a fluoroquinolone antibiotic, after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration was determined in sheep at a single dose of 5 mg/kg. The concentration-time data were analysed by compartmental (after IV dose) and non-compartmental (after IV, IM and SC administration) pharmacokinetic methods. Plasma concentrations of moxifloxacin were determined by high performance liquid chromatography with fluorescence detection. Steady-state volume of distribution (V_ss) and clearance (Cl) of moxifloxacin after IV administration were 2.03 ± 0.36 L/kg and 0.39 ± 0.04 L/h kg, respectively. Following IM and SC administration, moxifloxacin achieved maximum plasma concentration of 1.66 ± 0.62 mg/L and 0.90 ± 0.19 mg/L at 2.25 ± 0.88 h and 3.25 ± 1.17 h, respectively. The absolute bioavailabilities after IM and SC routes were 96.12 ± 32.70% and 102.20 ± 23.76%, respectively. From these data (kinetic parameters and absence of adverse reactions) moxifloxacin may be a potentially useful antibiotic in sheep.     

Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration

Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat moderate to moderately severe pain in humans. The present study investigated tramadol administration in horses by intravenous, intramuscular, oral as immediate-release and oral as sustained-release dosage-form routes. Seven horses were used in a four-way crossover study design in which racemic tramadol was administered at 2 mg/kg by each route of administration. Altogether, 23 blood samples were collected between 0 and 2880 min. The concentration of tramadol and its M1 metabolite were determined in the obtained plasma samples by use of an LC/MS/MS method and were used for pharmacokinetic calculations. Tramadol clearance, apparent volume of distribution at steady-state, mean residence time (MRT) and half-life after intravenous administration were 26+/-3 mL/min/kg, 2.17+/-0.52 L/kg, 83+/-10 min, and 82+/-10 min, respectively. The MRT and half-life after intramuscular administration were 155+/-23 and 92+/-14 min. The mean absorption time was 72+/-22 min and the bioavailability 111+/-39%. Tramadol was poorly absorbed after oral administration and only 3% of the administered dose was found in systemic circulation. The fate of the tramadol M1 metabolite was also investigated. M1 appeared to be a minor metabolite in horses, which could hardly be detected in plasma samples. The poor bioavailability after oral administration and the short half-life of tramadol may restrict its usefulness in clinical applications.     

Pharmacokinetics of azithromycin after intravenous and intramuscular administration to goats

Azithromycin is the first of a class of antimicrobial agents designated azalides. The aim of the present study was to investigate the disposition pharmacokinetics of azithromycin in goats and determine its bioavailability. A cross-over study was carried out in two phases separated by 30 days. Azithromycin was administered at a single dose of 20 mg/kg body weight by i.v. and i.m. routes. Plasma concentrations of azithromycin were determined by a modified agar diffusion bioassay. After a single i.v. dose plasma concentrations were best fitted to a three-compartment open model. A two-compartment open model with first-order absorption fitted best after i.m. administration. The values of the pharmacokinetic parameters after i.v. administration were: half-life 32.5 h, apparent volume of distribution at the steady-state 34.5 L/kg, clearance 0.85 L/kg. and mean residence time (MRT) 40.1 h. After i.m. administration half-life of 45.2 h, a MRT of 60.3 h, maximum plasma concentration 0.64 mg/L and a bioavalability 92.2% were obtained. The pharmacokinetic parameters of azithromycin after i.m. administration, principally its long half-life and high bioavailability, could provide an alternative to the oral route of administration in goats, although more studies are needed to establish a suitable pharmaceutical formulation, propose optimun dosage regimens, investigate clinical efficacy and study the tolerability of repeated doses.     

Pharmacokinetics of erythromycin after intravenous,intramuscular and oral administration to cats

The aim of this study was to characterise the pharmacokinetic properties of different formulations of erythromycin in cats. Erythromycin was administered as lactobionate (4 mg/kg intravenously (IV)), base (10 mg/kg, intramuscularly (IM)) and ethylsuccinate tablets or suspension (15 mg/kg orally (PO)). After IV administration, the major pharmacokinetic parameters were (mean ± SD): area under the curve (AUC)_(0–∞) 2.61 ± 1.52 μg h/mL; volume of distribution (V_z) 2.34 ± 1.76 L/kg; total body clearance (Cl_t) 2.10 ± 1.37 L/h kg; elimination half-life (t_½λ) 0.75 ± 0.09 h and mean residence time (MRT) 0.88 ± 0.13 h. After IM administration, the principal pharmacokinetic parameters were (mean ± DS): peak concentration (C_max), 3.54 ± 2.16 μg/mL; time of peak (T_max), 1.22 ± 0.67 h; t_½λ, 1.94 ± 0.21 h and MRT, 3.50 ± 0.82 h. The administration of erythromycin ethylsuccinate (tablets and suspension) did not result in measurable serum concentrations. After IM and IV administrations, erythromycin serum concentrations were above minimum inhibitory concentration (MIC)₉₀ = 0.5 μg/mL for 7 and 1.5 h, respectively. However, these results should be interpreted cautiously since tissue erythromycin concentrations have not been measured and can reach much higher concentrations than in blood, which may be associated with enhanced clinical efficacy.     

Pharmacokinetics of marbofloxacin after intravenous and intramuscular administration to ostriches

The pharmacokinetics of marbofloxacin was investigated after intravenous (IV) and intramuscular (IM) administration, both at a dose rate of 5 mg/kg BW, in six clinically healthy domestic ostriches. Plasma concentrations of marbofloxacin was determined by a HPLC/UV method. The high volume of distribution (3.22+/-0.98 L/kg) suggests good tissue penetration. Marbofloxacin presented a high clearance value (2.19+/-0.27 L/kgh), explaining the low AUC values (2.32+/-0.30 microgh/mL and 2.25+/-0.70 microgh/mL, after IV and IM administration, respectively) and a short half life and mean residence time (t(1/2 beta)=1.47+/-0.31 h and 1.96+/-0.35 h; MRT=1.46+/-0.02 h and 2.11+/-0.30 h, IV and IM, respectively). The absorption of marbofloxacin after IM administration was rapid and complete (C(max)=1.13+/-0.29 microg/mL; T(max)=0.36+/-0.071 h; MAT=0.66+/-0.22 h and F (%)=95.03+/-16.89).