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 intravenous fentanyl and buprenorphine in healthy greyhound dogs

The purpose of this study was to compare the pharmacokinetics of two highly protein‐bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half‐life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol–water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95–98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs.     

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.     

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.     

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 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 oral transmucosal and intramuscular dexmedetomidine combined with buprenorphine in cats

Plasma concentrations and pharmacokinetics of dexmedetomidine and buprenorphine after oral transmucosal (OTM) and intramuscular (i.m.) administration of their combination in healthy adult cats were compared. According to a crossover protocol (1‐month washout), a combination of dexmedetomidine (40 μg/kg) and buprenorphine (20 μg/kg) was given OTM (buccal cavity) or i.m. (quadriceps muscle) in six female neutered cats. Plasma samples were collected through a jugular catheter during a 24‐h period. Plasma dexmedetomidine and buprenorphine concentrations were determined by liquid chromatography–tandem mass spectrometry. Plasma concentration–time data were fitted to compartmental models. For dexmedetomidine and buprenorphine, the area under the plasma concentration–time curve (AUC) and the maximum plasma concentrations (C_max) were significantly lower following OTM than following i.m. administration. For buprenorphine, time to reach C_max was also significantly longer after OTM administration than after i.m. injection. Data suggested that dexmedetomidine (40 μg/kg) combined with buprenorphine (20 μg/kg) is not as well absorbed from the buccal mucosa site as from the intramuscular injection site.     

Plasma buprenorphine concentrations after the application of a 70 μg/h transdermal patch in dogs. Preliminary report

The objective of the present study was to evaluate the plasma concentrations and pharmacokinetics of buprenorphine after transdermal application in dogs ( n  = 4). A 70 μg/h transdermal buprenorphine patch was applied to the ventral abdomen of four healthy beagles. Blood samples were collected through a preplaced jugular catheter before and at 1, 2, 4, 8, 12, 24, 36, 48 and every 6 h until 108 h after the patch application. Plasma buprenorphine concentrations were measured using a ¹²⁵I-labelled radioimmunoassay (RIA) assay. No adverse effects were observed in any of the dogs. Concentrations of buprenorphine were detected in plasma after the application of the transdermal buprenorphine patch on the four experimental animals. Buprenorphine plasma concentrations increased during the first 36 h and then remained in the 0.7–1.0 ng/mL range during the study period. A decrease in plasma buprenorphine concentration was not observed during the study. Although analgesia could not be demonstrated the present study shows the ability of buprenorphine transdermal delivery systems developed for human use to deliver measurable concetrations of buprenorphine in dogs.     

Dose-related antinociceptive effects of intravenous buprenorphine in cats

The dose-related antinociceptive effects of intravenous (IV) buprenorphine were evaluated in cats. Thermal (TT) and mechanical threshold (MT) devices were used for nociceptive stimulation. After baseline threshold recordings, buprenorphine was administered IV (0.01, 0.02 or 0.04 mg/kg; B1, B2 and B4, respectively) in a randomised, blinded and cross-over study. Data were analysed by ANOVA (P < 0.05) using 95% confidence intervals (CI). TT increased 15, 30, 45 min and 1 (5.2 ± 2.7 °C), 2, 3 and 4 h after B1; 15, 30, 45 min and 1 (5.1 ± 3.9 °C) and 2 h after B2, and 15, 30, 45 min and 1 (5.4 ± 3.3 °C), 2, 3, 6 and 8 h after B4. MT increased 15 and 45 min after B2 (260 ± 171 mmHg), and 30 (209 ± 116 mmHg) and 45 min and 1 and 2 h after B4. At 45 min, MT values were significantly higher after B2 compared to B1 (P < 0.05). With MT, B2 and B4 produced more antinociception and longer duration of action than B1, respectively. No dose response to thermal stimulation was detected.     

Serum concentrations of buprenorphine after oral and parenteral administration in male mice

Buprenorphine is the most commonly used drug for peri-operative pain relief in laboratory rodents. The systemic concentrations of buprenorphine were measured in mice following administration intravenously (IV), subcutaneously (SC), orally by gavage and by voluntary ingestion, to determine the post-administration serum concentration of buprenorphine. Voluntarily ingested buprenorphine resulted in long-lasting high serum concentrations, as did oral gavage administration (24 h serum concentration: 110 ng h/mL for both routes of administration). In contrast, buprenorphine administered parenterally remained in the circulation for a substantially shorter time (24 h serum concentration for IV and SC were 40 ng h/mL and 30 ng h/mL, respectively). This marked difference was probably due to the higher dose used for oral administration, which is regarded necessary for sufficient analgesic effect, and to the slower absorption of the oral boli, as well as saturation of the hepatic buprenorphine metabolising pathways. Voluntary ingestion of buprenorphine was found to constitute a practical way to provide laboratory mice with efficient pain relief.     

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals

Buprenorphine is absorbed following sublingual administration, which would be a low‐stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3‐period, 5‐sequence, 3‐treatment crossover prospective study. Foals received 0.01–0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half‐life (t_1/2β 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.     

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 intravenous dexmedetomidine in the horse

The aim of the study was to describe the pharmacokinetics and selected pharmacodynamics of intravenous dexmedetomidine in horses. Eight adult horses received 5 μg/kg dexmedetomidine IV. Blood samples were collected before and for 10 h after drug administration to determine dexmedetomidine plasma concentrations. Pharmacokinetic parameters were calculated using noncompartmental analysis. Data from one outlier were excluded from the statistical summary. Behavioral and physiological responses were recorded before and for 6 h after dexmedetomidine administration. Dexmedetomidine concentrations decreased rapidly (elimination half‐life of 8.03 ± 0.84 min). Time of last detection varied from 30 to 60 min. Bradycardia was noted at 4 and 10 min after drug administration (26 ± 8 and 29 ± 8 beats/min respectively). Head height decreased by 70% at 4 and 10 min and gradually returned to baseline. Ability to ambulate was decreased for 60 min following drug administration, and mechanical nociceptive threshold was increased during 30 min. Blood glucose peaked at 30 min (134 ± 24 mg/dL) and borborygmi were decreased for the first hour after dexmedetomidine administration. Dexmedetomidine was quickly eliminated as indicated by the rapid decrease in plasma concentrations. Physiological, behavioral, and analgesic effects observed after dexmedetomidine administration were of short duration.     

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 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).     

Glucose and insulin response after intravenous and subcutaneous somatostatin administration in healthy horses

Equine metabolic syndrome (EMS) is prevalent in the equine population, and somatostatin analogs might be useful for diagnosis and/or treatment of EMS in horses. The purpose of this study was to evaluate the glucose and insulin responses to subcutaneous and intravenous administration of somatostatin. Six healthy research horses were included in this prospective study. An initial pilot study was performed to assess several different doses (10–22 µg/kg [4.5–10 µg/lb]) in two horses, then a final dosage of 22 µg/kg (10 µg/lb) was administered to six horses IV and SQ in a two‐period randomized cross‐over study performed over a 3‐month study period. Blood samples were collected for measurement of plasma insulin and glucose concentrations during a 24‐hr study period. Both IV and SQ somatostatin resulted in decreased insulin and increased glucose concentrations. SQ somatostatin resulted in a longer clinical effect, with return to baseline insulin occurring at 1.5 hr postadministration, versus 45 min for IV. Both IV and SQ administration of somatostatin to normal horses resulted in decreased insulin and increased glucose concentrations, likely due to suppression of insulin secretion by somatostatin. A more prolonged effect was seen following SQ administration as compared to IV administration, and no adverse effects were noted at varying doses. This study provides additional information regarding the effect of somatostatin administration on insulin and glucose concentrations in clinically healthy horses.     

Pharmacokinetic‐pharmacodynamic modelling of intravenous buprenorphine in conscious horses

ObjectiveDescribe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects.Study designSingle phase non-blinded study.AnimalsSix dedicated research horses, aged 3–10 years and weighing 480–515 kg.MethodsThermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 &; 60 minutes and 2, 4, 6, 8, 12 &; 24 hours post-administration of 10 μg kg⁻¹ buprenorphine IV. Intestinal motility was measured 1, 6, 12 &; 24 hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10 μg kg⁻¹ IV and 1, 2, 4, 6, 10, 15, 30, 45 &; 60 minutes, and 2, 4, 6, 8, 12 &; 24 hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration–time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model.ResultsPlasma buprenorphine concentrations were detectable to 480 minutes in all horses and to 720 minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15 minutes post-buprenorphine administration until the 8–12 hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0 Newtons (median: 4.4 N); and was associated with plasma buprenorphine concentrations in the range 0.34–2.45 ng mL⁻¹.Conclusions and clinical relevanceThe suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.     

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.     

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.     

The exogenous fluorophore,fluorescein, enables in vivo assessment of the gastrointestinal mucosa via confocal endomicroscopy: optimization of intravenous dosing in the dog model

This study described the pharmacokinetics of the intravenous fluorophore, fluorescein, and aimed to evaluate its utility for use in upper gastrointestinal confocal endomicroscopy (CEM). Six healthy, mature, mixed‐breed dogs were anesthetized and then dosed intravenously with fluorescein at 15 mg/kg. Blood samples were collected at predetermined time‐points. Dogs were examined by upper gastrointestinal confocal endomicroscopy and monitored for adverse effects. Plasma fluorescein concentrations were measured using high‐performance liquid chromatography (HPLC) with UV/Vis detection. Mean plasma concentration at 5 min was 57.6 ± 18.2 mg/L, and plasma concentrations decreased bi‐exponentially thereafter with a mean concentration of 2.5 mg/L ± 1.26 at 120 min. Mean terminal plasma elimination half‐life (t_½β) was 34.8 ± 8.94 min, and clearance was 9.1 ± 3.0 mL/kg/min. Apparent volume of distribution at steady‐state was 0.3 ± 0.06 L/kg. Fluorescein provided optimal fluorescent contrast to enable in vivo histologically equivalent evaluation of topologic mucosal morphology within the first 30 min following intravenous administration. Adverse effects were not observed. Based upon the calculated clearance, a constant rate infusion at a rate of 0.18 mg/kg/min is predicted to be adequate, following an initial loading dose (2 mg/kg), to maintain plasma concentration at 20 mg/L for optimal CEM imaging during the study period.