Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site

ObjectiveTo describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration.Study designRandomized crossover experiment; prospective study.AnimalsEleven healthy adult horses between 6 and 20 years of age and weighing 487–592 kg.MethodsIn the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg^?1) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg^?1 SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility.ResultsFollowing IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg^?1 minute^?1 and volume of distribution at steady-state was 3.16 ± 0.65 L kg^?1. Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported.Conclusions and clinical relevanceBuprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.     

Bioavailability of morphine,methadone, hydromorphone,and oxymorphone following buccal administration in cats

Buccal administration of buprenorphine is commonly used to treat pain in cats. It has been argued that absorption of buprenorphine through the buccal mucosa is high, in part due to its pKa of 8.24. Morphine, methadone, hydromorphone, and oxymorphone have a pKa between 8 and 9. This study characterized the bioavailability of these drugs following buccal administration to cats. Six healthy adult female spayed cats were used. Buccal pH was measured prior to drug administration. Morphine sulfate, 0.2 mg/kg IV or 0.5 mg/kg buccal; methadone hydrochloride, 0.3 mg/kg IV or 0.75 mg/kg buccal; hydromorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal; or oxymorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal were administered. All cats received all treatments. Arterial blood was sampled immediately prior to drug administration and at various times up to 8 h thereafter. Bioavailability was calculated as the ratio of the area under the time–concentration curve following buccal administration to that following IV administration, each indexed to the administered dose. Mean ± SE (range) bioavailability was 36.6 ± 5.2 (12.7–49.5), 44.2 ± 7.9 (18.7–70.5), 22.4 ± 6.9 (6.4–43.4), and 18.8 ± 2.0 (12.9–23.5)% for buccal administration of morphine, methadone, hydromorphone, and oxymorphone, respectively. Bioavailability of methadone was significantly higher than that of oxymorphone.     

Pharmacokinetics of tobramycin following intravenous,intramuscular, and intra‐articular administration in healthy horses

The objectives of this study were to examine the pharmacokinetics of tobramycin in the horse following intravenous (IV), intramuscular (IM), and intra‐articular (IA) administration. Six mares received 4 mg/kg tobramycin IV, IM, and IV with concurrent IA administration (IV+IA) in a randomized 3‐way crossover design. A washout period of at least 7 days was allotted between experiments. After IV administration, the volume of distribution, clearance, and half‐life were 0.18 ± 0.04 L/kg, 1.18 ± 0.32 mL·kg/min, and 4.61 ± 1.10 h, respectively. Concurrent IA administration could not be demonstrated to influence IV pharmacokinetics. The mean maximum plasma concentration (C_max) after IM administration was 18.24 ± 9.23 μg/mL at 1.0 h (range 1.0–2.0 h), with a mean bioavailability of 81.22 ± 44.05%. Intramuscular administration was well tolerated, despite the high volume of drug administered (50 mL per 500 kg horse). Trough concentrations at 24 h were below 2 μg/mL in all horses after all routes of administration. Specifically, trough concentrations at 24 h were 0.04 ± 0.01 μg/mL for the IV route, 0.04 ± 0.02 μg/mL for the IV/IA route, and 0.02 ± 0.02 for the IM route. An additional six mares received IA administration of 240 mg tobramycin. Synovial fluid concentrations were 3056.47 ± 1310.89 μg/mL at 30 min after administration, and they persisted for up to 48 h with concentrations of 14.80 ± 7.47 μg/mL. Tobramycin IA resulted in a mild chemical synovitis as evidenced by an increase in synovial fluid cell count and total protein, but appeared to be safe for administration. Monte Carlo simulations suggest that tobramycin would be effective against bacteria with a minimum inhibitory concentration (MIC) of 2 μg/mL for IV administration and 1 μg/mL for IM administration based on C_max:MIC of 10.     

The pharmacokinetics and analgesic effects of extended‐release buprenorphine administered subcutaneously in healthy dogs

Buprenorphine is a partial μ agonist opioid used for analgesia in dogs. An extended‐release formulation (ER‐buprenorphine) has been shown to provide effective analgesia for 72 hr in rats and mice. Six healthy mongrel dogs were enrolled in a randomized, blinded crossover design to describe and compare the pharmacokinetics and pharmacodynamics of ER‐buprenorphine administered subcutaneous at 0.2 mg/kg (ER‐B) and commercially available buprenorphine for injection intravenously at 0.02 mg/kg (IV‐B). After drug administration, serial blood samples were collected to measure plasma buprenorphine concentrations using liquid chromatography/mass spectrometry detection. Heart rate, respiratory rate, body temperature, sedation score, and thermal threshold latency were recorded throughout the study. Median (range) terminal half‐life, time to maximum concentration, and maximum plasma concentration of ER‐buprenorphine were 12.74 hr (10.43–18.84 hr), 8 hr (4–36 hr), and 5.00 ng/ml (4.29–10.98 ng/ml), respectively. Mild bradycardia, hypothermia, and inappetence were noted in both groups. Thermal threshold latency was significantly prolonged compared to baseline up to 12 hr and up to 72 hr in IV‐B and ER‐B, respectively. These results showed that ER‐buprenorphine administered at a dose of 0.2 mg/kg resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration.     

Comparative pharmacokinetics of minocycline in foals and adult horses

The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6‐ to 9‐week‐old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross‐over design. Five additional oral doses were administered at 12‐h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography–tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells. After i.v. administration to foals, minocycline had a mean (±SD) elimination half‐life of 8.5 ± 2.1 h, a systemic clearance of 113.3 ± 26.1 mL/h/kg, and an apparent volume of distribution of 1.24 ± 0.19 L/kg. Pharmacokinetic variables determined after i.v. administration to adult horses were not significantly different from those determined in foals. Bioavailability was significantly higher in foals (57.8 ± 19.3%) than in adult horses (32.0 ± 18.0%). Minocycline concentrations in PELF were higher than in other body fluids. Oral minocycline dosed at 4 mg/kg every 12 h might be adequate for the treatment of susceptible bacterial infections in foals.     

Pharmacokinetics of butorphanol and evaluation of physiologic and behavioral effects after intravenous and intramuscular administration to neonatal foals

Background: Despite frequent clinical use, information about the pharmacokinetics (PK), clinical effects, and safety of butorphanol in foals is not available. Objectives: The purpose of this study was to determine the PK of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals. Animals: Six healthy mixed breed pony foals between 3 and 12 days of age were used. Methods: In a 3‐way crossover design, foals received butorphanol (IV and IM, at 0.05 mg/kg) and IV saline (control group). Butorphanol concentrations were determined by high‐performance liquid chromatography and analyzed using a noncompartmental PK model. Physiologic data were obtained at specified intervals after drug administration. Pedometers were used to evaluate locomotor activity. Behavioral data were obtained using a 2‐hour real‐time video recording. Results: The terminal half‐life of butorphanol was 2.1 hours and C₀ was 33.2 ± 12.1 ng/mL after IV injection. For IM injection, C_max and T_max were 20.1 ± 3.5 ng/mL and 5.9 ± 2.1 minutes, respectively. Bioavailability was 66.1 ± 11.9%. There were minimal effects on vital signs. Foals that received butorphanol spent significantly more time nursing than control foals and appeared sedated. Conclusions and Clinical Importance: The disposition of butorphanol in neonatal foals differs from that in adult horses. The main behavioral effects after butorphanol administration to neonatal foals were sedation and increased feeding behavior.     

Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats,and effects on thermal threshold

This study reports the pharmacokinetics of buprenorphine, following i.v. and buccal administration, and the relationship between buprenorphine concentration and its effect on thermal threshold. Buprenorphine (20 μg/kg) was administered intravenously or buccally to six cats. Thermal threshold was determined, and arterial blood sampled prior to, and at various times up to 24 h following drug administration. Plasma buprenorphine concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to the time–concentration data. Pharmacokinetic/pharmacodynamic models were fitted to the concentration‐thermal threshold data. Thermal threshold was significantly higher than baseline 44 min after buccal administration, and 7, 24, and 104 min after i.v. administration. A two‐ and three‐compartment model best fitted the data following buccal and i.v. administration, respectively. Following i.v. administration, mean ± SD volume of distribution at steady‐state (L/kg), clearance (mL·min/kg), and terminal half‐life (h) were 11.6 ± 8.5, 23.8 ± 3.5, and 9.8 ± 3.5. Following buccal administration, absorption half‐life was 23.7 ± 9.1 min, and terminal half‐life was 8.9 ± 4.9 h. An effect‐compartment model with a simple effect maximum model best predicted the time‐course of the effect of buprenorphine on thermal threshold. Median (range) k_e0 and EC50 were 0.003 (0.002–0.018)/min and 0.599 (0.073–1.628) ng/mL (i.v.), and 0.017 (0.002–0.023)/min and 0.429 (0.144–0.556) ng/mL (buccal).     

Pharmacokinetics of metronidazole in foals: influence of age within the neonatal period

Neonatal foals have unique pharmacokinetics, which may lead to accumulation of certain drugs when adult horse dosage regimens are used. Given its lipophilic nature and requirement for hepatic metabolism, metronidazole may be one of these drugs. The purpose of this study was to determine the pharmacokinetic profiles of metronidazole in twelve healthy foals at 1–2.5 days of age when administered as a single intravenous (IV) and intragastric (IG) dose of 15 mg/kg. Foals in the intravenous group were studied a second time at 10–12 days of age to evaluate the influence of age on pharmacokinetics within the neonatal period. Blood samples were collected at serial time points after metronidazole administration. Metronidazole concentration in plasma was measured using LC‐MS. Pharmacokinetic parameters were determined using noncompartmental analysis and compared between age groups. At 1–2.5 days of age, the mean peak plasma concentration after IV infusion was 18.79 ± 1.46 μg/mL, elimination half‐life was 11.8 ± 1.77 h, clearance was 0.84 ± 0.13 mL/min/kg and the volume of distribution (steady‐state) was 0.87 ± 0.07 L/kg. At 10–12 days of age, the mean peak plasma concentration after IV infusion was 18.17 ± 1.42 μg/mL, elimination half‐life was 9.07 ± 2.84 h, clearance was 1.14 ± 0.21 mL/min/kg and the volume of distribution (steady‐state) was 0.88 ± 0.06 L/kg. Oral approximated bioavailability was 100%. Cmax and T_max after oral dosing were 14.85 ± 0.54 μg/mL and 1.75 (1–4) h, respectively. The elimination half‐life was longer and clearance was reduced in neonatal foals at 1–2.5 days as compared to 10–12 days of age (P = 0.006, P = 0.001, respectively). This study warrants consideration for altered dosing recommendations in foals, especially a longer interval (12 h).     

Pharmacokinetic parameters for single‐ and multi‐dose regimens for subcutaneous administration of a high‐dose ceftiofur crystalline‐free acid to neonatal foals

The objective of this study was to determine the pharmacokinetics of single‐ and multi‐dose ceftiofur crystalline‐free acid (CCFA) administered subcutaneously at a dose of 13.2 mg/kg to 12 neonatal foals 1–3 days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48‐h intervals. Blood samples were collected at pre‐determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high‐performance liquid chromatography. Following single‐dose administration of CCFA, the mean ± standard deviation maximum observed plasma concentration was 3.1 ± 0.6 μg/mL and observed time to maximal plasma concentration was 14.0 ± 4.9 h. Following multi‐dose administration of CCFA, the mean ±standard deviation times above CFAE concentrations of ≥0.5 μg/mL and ≥2.0 μg/mL were 192.95 ± 15.86 h and 78.80 ± 15.31 h, respectively. The mean ± standard deviation area under the concentration vs time curve (AUC_0→∝) was 246.2 ± 30.7 h × μg/mL and 172.7 ± 27.14 h × μg/mL following single‐ and multi‐dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2 mg/kg in neonatal foals was clinically well‐ tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi‐dose administration of four doses at dosing interval of 48 h between treatments maintains appropriate therapeutic concentrations in neonatal foals.     

Pharmacokinetics of transdermal flunixin in sows

The objective of this study was to describe the pharmacokinetics (PK) of flunixin in 12 nonlactating sows following transdermal (TD) flunixin (3.33 mg/kg) and intravenous (IV; 2.20 mg/kg) flunixin meglumine (FM) administration using a crossover design with a 10‐day washout period. Blood samples were collected postadministration from sows receiving IV FM (3, 6, 10, 20, 40 min and 1, 3, 6, 12, 16, 24, 36, and 48 hr) and from sows receiving TD flunixin (10, 20, 40 min and 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hr). Liquid chromatography and mass spectrometry were used to determine plasma flunixin concentrations, and noncompartmental methods were used for PK analysis. The geometric mean ± SD area under the plasma concentration–time curve (AUC) following IV injection was 26,820.59 ± 9,033.88 and 511.83 ± 213.98 hr ng/ml for TD route. Mean initial plasma concentration (C₀) was 26,279.70 ± 3,610.00 ng/ml, and peak concentration (C_max) was 14.61 ± 7.85 ng/ml for IV and TD administration, respectively. The percent mean bioavailability of TD flunixin was 1.55 ± 1.00. Our results demonstrate that topical administration is not an efficient route for delivering flunixin in mature sows.     

Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos)

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross‐over design with a washout period between doses. Mean (±SD) C_max following IM injection was 1.6 (±0.8) µg/ml with T_max at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (V_D) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min^?1 kg^?1. Elimination half‐lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.     

Plasma and synovial fluid pharmacokinetics of a single intravenous dose of meropenem in adult horses

The objective of this study was to determine the pharmacokinetics of meropenem in horses after intravenous (IV) administration. A single IV dose of meropenem was administered to six adult horses at 10 mg/kg. Plasma and synovial fluid samples were collected for 6 hr following administration. Meropenem concentrations were determined by bioassay. Plasma and synovial fluid data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean ± SD values for elimination half‐life, volume of distribution at steady‐state, and clearance after IV administration for plasma samples were 0.78 ± 0.176 hr, 136.1 ± 19.69 ml/kg, and 165.2 ± 29.72 ml hr^‐1 kg^?1, respectively. Meropenem in synovial fluid had a slower elimination than plasma with a terminal half‐life of 2.4 ± 1.16 hr. Plasma protein binding was estimated at 11%. Based on a 3‐compartment open pharmacokinetic model of simultaneously fit plasma and synovial fluid, dosage simulations were performed. An intermittent dosage of meropenem at 5 mg/kg IV every 8 hr or a constant rate IV infusion at 0.5 mg/kg per hour should maintain adequate time above the MIC target of 1 μg/ml. Carbapenems are antibiotics of last resort in humans and should only be used in horses when no other antimicrobial would likely be effective.     

Pharmacokinetics of florfenicol and thiamphenicol in ducks

The pharmacokinetics of florfenicol (FF) and thiamphenicol (TP) after single intravenous (IV) and oral (PO) administration was investigated in Mulard ducks. Both antibiotics were administered at a dose of 30 mg/kg body weight, and their concentrations in plasma samples were assayed using high‐performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were calculated using a noncompartmental method. After IV administration, significant differences were found for the mean residence time (2.25 ± 0.21 hr vs. 2.83 ± 0.50 hr for FF and TP, respectively) and the general half‐life (1.56 ± 0.15 hr vs. 1.96 ± 0.35 hr for FF and TP, respectively) indicating slightly slower elimination of TP as compared to FF. The clearance, however, was comparable (0.30 ± 0.07 L/hr/kg for FF and 0.26 ± 0.04 L/hr/kg for TP). The mean volume of distribution was below 0.7 L/kg for both drugs. Pharmacokinetics after PO administration was very similar for FF and TP suggesting minor clinical importance of the differences found in the IV study. Both antimicrobials showed rapid absorption and bioavailability of more than 70% indicating that PO route should be an efficient method of FF and TP administration to ducks under field conditions.     

Pharmacokinetics of single doses of maropitant citrate in adult horses

The neurokinin‐1 (NK) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood and likely under‐recognized in horses. Use of NK‐1 receptor antagonists in horses has not been reported. The purpose of this study was to determine the pharmacokinetic profile of maropitant in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant concentrations were measured using LC‐MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant concentration 3 min after IV administration was 800 ± 140 ng/ml, elimination half‐life was 10.37 ± 2.07 h, and volume of distribution was 6.54 ± 1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half‐life was 9.64 ± 1.27 hr. Oral bioavailability was variable at 13.3 ± 5.3%. Maropitant concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half‐life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant in horses.     

Pharmacokinetics of thymoquinone in layer chickens following oral and intravenous administration

Thymoquinone (TQ) is the major constituent of Nigella sativa and known to possess a variety of pharmacological effects. This study was designed to evaluate the pharmacokinetic profile of TQ following oral (PO) and intravenous (IV) administration in layer chickens. The layer chickens were equally divided into two groups (six chickens in each group, total 12 chickens), and TQ was administered via PO and IV routes. For PO route, the dose was 20 mg/kg b.w. and for IV route, 5 mg/kg b.w. was administered, respectively. A sensitive and accurate High‐Performance Liquid Chromatography (HPLC) technique was validated for the quantification of TQ from plasma. The limit of detection (LOD) and limit of quantification (LOQ) were 0.02 µg/ml and 0.05 µg/ml, respectively with >80% recovery. Maximum plasma concentration (C_max) following PO and IV administration was 8.805 and 4.497 µg/ml, respectively, while time to reach at maximum concentration (T_max) was 1 and 0.1 hr, respectively. The elimination half‐lives were recorded as 1.02 and 0.978 hr, whereas the mean residence times were 1.79 and 1.036 hr following both PO and IV administration, respectively. The 85% PO bioavailability was indicative that TQ could be used for various therapeutic purposes in layer chickens.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Pharmacokinetics,pharmacodynamics, and metabolism of acepromazine following intravenous,oral, and sublingual administration to exercised Thoroughbred horses

Acepromazine is a tranquilizer used commonly in equine medicine. This study describes serum and urine concentrations and the pharmacokinetics and pharmacodynamics of acepromazine following intravenous, oral, and sublingual (SL) administration. Fifteen exercised adult Thoroughbred horses received a single intravenous, oral, and SL dose of 0.09 mg/kg of acepromazine. Blood and urine samples were collected at time 0 and at various times for up to 72 hr and analyzed for acepromazine and its two major metabolites (2‐(1‐hydroxyethyl) promazine and 2‐(1‐hydroxyethyl) promazine sulfoxide) using liquid chromatography–tandem mass spectrometry. Acepromazine was also incubated in vitro with whole equine blood and serum concentrations of the parent drug and metabolites determined. Acepromazine was quantitated for 24 hr following intravenous administration and 72 hr following oral and SL administration. Results of in vitro incubations with whole blood suggest additional metabolism by RBCs. The mean ± SEM elimination half‐life was 5.16 ± 0.450, 8.58 ± 2.23, and 6.70 ± 2.62 hr following intravenous, oral, and SL administration, respectively. No adverse effects were noted and horses appeared sedate as noted by a decrease in chin‐to‐ground distance within 5 (i.v.) or 15 (p.o. and SL) minutes postadministration. The duration of sedation lasted 2 hr. Changes in heart rate were minimal.     

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

The purpose of this study was to determine the pharmacokinetics of cefquinome (CFQ) following single and repeated subcutaneous (SC) administrations in sheep. Six clinically healthy, 1.5 ± 0.2 years sheep were used for the study. In pharmacokinetic study, the crossover design in three periods was performed. The withdrawal interval between the study periods was 15 days. In first period, CFQ (Cobactan, 2.5%) was administered by an intravenous (IV) bolus (3 sheep) and SC (3 sheep) injections at 2.5 mg/kg dose. In second period, the treatment administration was repeated via the opposite administration route. In third period, CFQ was administrated subcutaneously to each sheep (n = 6) at a dose of 2.5 mg/kg q. 24 hr for 5 days. Plasma concentrations of CFQ were measured using the HPLC‐UV method. Pharmacokinetic parameters were calculated using non‐compartmental methods. The elimination half‐life and mean residence time of CFQ after the single SC administration were longer than IV administration (p < 0.05). Bioavailability (F%) of CFQ following the single SC administration was 123.51 ± 11.54%. The area under the curve (AUC_0‐∞) and peak concentration following repeated doses (last dose) were higher than those observed after the first dose (p < 0.05). CFQ accumulated after repeated SC doses. CFQ can be given via SC at a dose of 2.5 mg/kg every 24 hr for the treatment of infections caused by susceptible pathogens, which minimum inhibitory concentration is ≤1.0 μg/ml in sheep.     

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 furosemide administered 4 and 24 hours prior to high‐speed exercise in horses

Furosemide is a diuretic agent used commonly in racehorses to attenuate the bleeding associated with exercise‐induced pulmonary hemorrhage (EIPH). The current study describes serum and urine concentrations and the pharmacokinetics of furosemide following administration at 4 and 24 hrs prior to maximal exercise. Eight exercised adult Thoroughbred horses received a single IV administration of 250 mg of furosemide at 4 and 24 hrs prior to maximal exercise on a high‐speed treadmill. Blood and urine samples were collected at time 0 and at various times for up to 72 hrs and furosemide concentrations determined using liquid chromatography–tandem mass spectrometry. Serum furosemide concentrations remained above the LOQ (0.05 ng/ml) for 36 hrs in 3/8 and 1/8 horses in the 4‐ and 24‐hrs groups, respectively. Serum concentration data were best fit by a two‐compartment model. There was not a significant difference in the volume of distribution at steady‐state (0.594 ± 0.178 [4 hrs] and 0.648 ± 0.147 [24 hrs] L/kg) or systemic clearance (0.541 ± 0.094 [4 hrs] and 0.617 ± 0.114 [24 hrs] L/hrs/kg) between horses that were exercised at 4‐ and 24 hrs postdrug administration. The mean ± SD elimination half‐life was 3.12 ± 0.387 and 3.23 ± 0.407 hrs following administration at 4 and 24 hrs prior to exercise, respectively.