Evaluation of the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in fed and fasted Greyhound dogs

This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 h after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline C_MAX for the remaining fasted dogs (n = 3) was 22.8–64.5 ng/mL compared to 30.6–127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUC_INF for the three fasted dogs was 167–720 h·ng/mL compared to 287–1146 h·ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69–91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R² = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.     

Pharmacokinetics of S-ketamine and R-ketamine and their active metabolites after racemic ketamine or S-ketamine intravenous administration in dogs sedated with medetomidine

ObjectiveTo assess the differences in the pharmacokinetic profiles of S-ketamine, R-ketamine and their metabolites, S-norketamine and R-norketamine, and to measure relevant physiologic variables after intravenous administration of racemic (RS) ketamine or S-ketamine alone in Beagle dogs sedated with medetomidine.Study designExperimental, blinded and randomized crossover study.AnimalsA total of six (three female and three male) adult Beagle dogs.MethodsMedetomidine (450 μg m^–2) was administered intramuscularly, followed by either S-ketamine (2 mg kg^–1) or RS-ketamine (4 mg kg^–1) 20 minutes later, both administered intravenously. Blood samples were collected before medetomidine administration and at multiple time points 1–900 minutes following the ketamine administration. Plasma samples were analysed using liquid chromatography–tandem mass spectrometry. Heart rate, respiratory rate, noninvasive blood pressure, haemoglobin saturation with oxygen and body temperature were measured at baseline, before ketamine administration, and 1, 2, 5, 10, 15, 20 and 30 minutes after ketamine administration. All cardiovascular variables, blood glucose, haemoglobin and lactate concentrations were analysed using different linear mixed effects models; the significance was set at p < 0.05.ResultsS-ketamine showed a two-compartment kinetic profile; no statistically significant differences were observed between its concentrations or in the calculated pharmacokinetic parameters following S- or RS-ketamine. When the racemic mixture was administered, no differences were detected between R- and S-ketamine concentrations, but the area under the curve (AUC) for R-norketamine was significantly lower than that for S-norketamine. Clinically relevant physiologic variables did not show statistically significant differences following the administration of the racemic mixture or of S-ketamine alone.Conclusions and clinical relevanceThis study performed in dogs showed that RS-ketamine and S-ketamine combined with medetomidine showed enantioselective pharmacokinetics as S- and R-norketamine AUCs were different, but S-ketamine levels were identical.     

Pharmacokinetics of oral terbinafine in horses and Greyhound dogs

The objective of the study was to assess the pharmacokinetics of terbinafine administered orally to horses and Greyhound dogs. A secondary objective was to assess terbinafine metabolites. Six healthy horses and six healthy Greyhound dogs were included in the pharmacokinetic data. The targeted dose of terbinafine was 20 and 30 mg/kg for horses and dogs, respectively. Blood was collected at predetermined intervals for the quantification of terbinafine concentrations with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.1 and 8.6 h for horses and Greyhounds, respectively. The mean maximum plasma concentration was 0.31 and 4.01 μg/mL for horses and Greyhounds, respectively. The area under the curve (to infinity) was 1.793 h·μg/mL for horses and 17.253 h·μg/mL for Greyhounds. Adverse effects observed in one study horse included pawing at the ground, curling lips, head shaking, anxiety and circling, but these resolved spontaneously within 30 min of onset. No adverse effects were noted in the dogs. Ions consistent with carboxyterbinafine, n-desmethylterbinafine, hydroxyterbinafine and desmethylhydroxyterbinafine were identified in horse and Greyhound plasma after terbinafine administration. Further studies are needed assessing the safety and efficacy of terbinafine in horses and dogs.     

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs

Rung, K., Riond, J.-L. & Wanner, M. Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs. J. vet
Four dogs were given 5 mg/kg body weight enrofloxacin intravenously (i.v.) and orally (p.o.) in a cross-over study. Plasma concentrations of the active ingredient enrofloxacin and its main metabolite ciprofloxacin were determined by a reversed phase liquid chromatographic method. Pharmacokinetic parameters of both substances were calculated by use of statistical moments and were compared to those of enrofloxacin described in the veterinary literature. Mean enrofloxacin t _½λZ was 2.4 h, mean Cl_s was 27.1 ml/min-kg, and mean V_ss was 7.0 1/kg. After i.v. and p.o. administration, concentrations of ciprofloxacin exceeding minimal inhibitory concentrations of several microorganisms were reached (C_max= 0.2 ng/ml, max = 2.2 h after intravenous administration; C_max= 0.2 (ig/ml, t _max= 3.6 h after oral administration). A considerable part of the antimicrobial activity is due to ciprofloxacin, the main metabolite of enrofloxacin.     

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 of gemcitabine and its primary metabolite in dogs after intravenous infusion

Gemcitabine is a relatively new chemotherapeutic compound used to treat a variety of cancers in dogs. Previous work presented in a companion paper explored the plasma kinetics of gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), in dogs after an intravenous bolus gemcitabine dose and demonstrated the saturation of intracellular dFdCTP (2',2'-difluorodeoxycytidine 5'-triphosphate) occurs in vitro with increasing extracellular gemcitabine exposure in canine melanoma cells. In this study, the plasma pharmacokinetics (PKs) of gemcitabine and dFdU are further explored after gemcitabine doses of 10, 30, and 60 mg/kg administered by intravenous infusion with a loading dose. Gemcitabine displayed linear PKs, while the kinetics of dFdU were not dose proportional. The overall clearance, volume of distribution at steady-state, and terminal elimination half-life (t(1/2)) for gemcitabine were 0.421 L/h.kg, 0.822 L/kg, and 1.49 h, respectively. Plasma concentrations of dFdU peaked at approximately 2 h postdosing and had a t(1/2) of 14.9 h.     

Pharmacokinetics of topically applied ciprofloxacin in tears of mesocephalic and brachycephalic dogs

OBJECTIVE: To evaluate the pharmacokinetics of ophthalmic ciprofloxacin in the tear film of normal mesocephalic and brachycephalic dogs. ANIMALS STUDIED: Twenty mesocephalic dogs and 15 brachycephalic dogs. PROCEDURES: Thirty-five microliters of ciprofloxacin were placed on the cornea of both eyes of each dog. Five brachycephalic dogs were used twice. A tear-test strip placed in the ventral cul de sac for 30 s was used to obtain samples. The tear film of each eye was sampled once at eight time-points post administration, resulting in five samples at each time-point. Samples were evaluated using high performance liquid chromatography. Data from the two skull types were compared using the unpaired two-tailed t-test. RESULTS: The mean concentration of ciprofloxacin in the tears of mesocephalic dogs was 192.8 +/- 269.97, 140.6 +/- 91.06, 56.60 +/- 28.47, 13.6 +/- 6.3, 43.25 +/- 59.71, 16.6 +/- 10.62, 15.6 +/- 13.16 and 6.25 +/- 9.84 microg/g at 5, 10, 15, 30 min and 1, 2, 4 and 6 h, respectively. The mean concentration of ciprofloxacin in the tears of brachycephalic dogs was 272.6 +/- 106.21, 144.4 +/- 142.32, 131.2 +/- 147.07, 75 +/- 80.07, 40.8 +/- 30.35, 35 +/- 21.98, 52.75 +/- 51.87 and 8.6 +/- 12.10 microg/g at 5, 10, 15, 30 min and 1, 2, 4 and 6 h, respectively. There was no statistical difference in tear concentration at any time-point between skull types. CONCLUSIONS: Topical application of ciprofloxacin resulted in a mean tear concentration of ciprofloxacin that remained above the MIC(90) levels for most pathogenic bacteria for 6 h in normal mesocephalic and brachycephalic dogs.     

Pharmacokinetics and pharmacodynamics of oral acetaminophen in combination with codeine in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetic and antinociceptive effects of an acetaminophen/codeine combination administered orally to six healthy greyhounds. Antinociception was assessed using an electronic von Frey (vF) device as a mechanical/pressure model. Acetaminophen was administered at a dose of 600 mg (14.4–23.1 mg/kg) and codeine phosphate at 90 mg (2.1–3.3 mg/kg) equivalent to 67.5 mg codeine base (1.6–2.5 mg/kg). The geometric mean maximum plasma concentrations of acetaminophen, codeine, and codeine‐6‐glucuronide were 7.95 μg/mL, 11.0 ng/mL, and 3819 ng/mL, respectively. Morphine concentrations were <1 ng/mL. The terminal half‐lives of acetaminophen, codeine, and codeine‐6‐glucuronide were 0.94, 1.71, and 3.12 h. There were no significant changes in vF thresholds, except at 12 h which decreased on average by 17% compared to baseline. The decrease in vF thresholds at 12 h could be due to aversion, hyperalgesia, or random variability. The lack of antinociception in this study could be due to a true lack of antinociception, lack of model sensitivity, or specificity. Further studies using different models (including clinical trials), different dog breeds, multiple dose regimens, and a range of dosages are needed prior to recommended use or concluding lack of efficacy for oral acetaminophen/codeine in dogs.     

Fractionated oral dosing and its effect on cyclophosphamide pharmacokinetics in dogs with high-grade multicentric lymphoma

Cyclophosphamide (CP) is an alkylating agent commonly included in multi-drug treatment protocols for canine cancer. As a prodrug, CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. CP is frequently administered in a fractionated manner, with the total dose given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however canine pharmacokinetic studies of CP dose fractionation are lacking. The study objective was to evaluate the pharmacokinetics of fractionated oral CP dosing at a dose of 200–250 mg/m² over 3 to 4 days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in eight dogs following the first and last doses to assess for auto-induction of CP metabolism. No significant difference in the rate of CP elimination between first and last doses were detected (0.73 ± 0.46 vs. 1.22 ± 0.5 h⁻¹; p = .125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9 ± 2.1 vs. 7.9 ± 6.4 h × ng/ml; p = .936). These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, standard bolus dosing and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered a dose of 200–250 mg/m².     

Pharmacokinetics of deflazacort in rabbits after intravenous and oral administration and its interaction with erythromycin

The pharmacokinetic of deflazacort after intravenous and oral administration and the effect of erythromycin on the disposition of deflazacort in rabbits were investigated. A parallel study was carried out in twelve rabbits. The plasma concentration–time profiles of deflazacort were determined after intravenous and oral administration of single dosages of 5 mg/kg in the presence and absence (baseline) of multiple dose erythromycin regimens. Plasma concentrations of 21‐desacetyldeflazacort were determined by HPLC. Plasma concentration–time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The t_½λz values following intravenous and oral administration were 3.67 and 4.96 hr, respectively. The apparent volume of distribution at steady‐state (V_ss) was 4.08 ± 0.31 L/kg, this value indicates that deflazacort is widely distributed into the extravascular tissues. Moreover, bioavailability after oral administration of deflazacort (F = 87.48%) was high. Pharmacokinetic analysis after both routes of administration revealed a significant reduction in total body clearance, a significant increase in mean residence time, half‐life and plasma concentrations of the steroid in the presence of multiple dose erythromycin. The results indicated the influence of the erythromycin on deflazacort disposition, which is consistent with a pharmacokinetic‐type interaction in the elimination of the drug from the body. Moreover, this interaction should be considered to avoid adverse effects when using both drugs concomitantly.     

青蒿琥酯活性代谢产物双氢青蒿素的牛体代谢动力学

健康奶牛与黄牛各5头,分别单剂量静注5mg/kg和10mg/kg青蒿琥酯,用TLC法测定青蒿琥酯的活性代谢产物双氢青蒿素在牛血中的浓度.经统计矩方法计算分析双氢青蒿素的主要药动学参数,并与青蒿琥酯原药的药动学参数进行了比较.     

Pharmacokinetics of gemcitabine and its primary metabolite in dogs after intravenous bolus dosing and its in vitro pharmacodynamics

Gemcitabine is a chemotherapeutic agent used to treat a variety of cancers in humans and dogs. In this study, the plasma pharmacokinetics of gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), were investigated in dogs after intravenous bolus gemcitabine doses of 3, 10, and 30 mg/kg. Furthermore, the intracellular accumulation of the active metabolite gemcitabine triphosphate, as a surrogate pharmacodynamic endpoint, was also determined in vitro in canine melanoma cells. Gemcitabine was characterized by linear kinetics, while dFdU dose proportionality remains unknown. The average gemcitabine clearance was 0.560 L/h.kg and volume of distribution at steady-state of 1.27 L/kg. The average terminal elimination half-life, depending on dose, ranged from 1.75 to 3.23 h. Plasma concentrations of dFdU peaked at approximately 2 h post-dosing. In vitro intracellular gemcitabine triphosphate accumulation was saturated with increasing extracellular gemcitabine concentrations. These data can be used to rationally design gemcitabine dosage regimes for canine oncology patients and as a basis for future investigations on the in vivo intracellular accumulation of gemcitabine triphosphate in dogs.     

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.     

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 enrofloxacin and its metabolite ciprofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration

To the best of the authors’ knowledge, pharmacokinetic information to establish suitable therapeutic plans for freshwater crocodiles is limited. Therefore, the purpose of this study was to clarify the pharmacokinetic characteristics of enrofloxacin (ENR) in freshwater crocodiles, Crocodylus siamensis, following single intravenous and intramuscular administration at a dosage of 5 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 168 hr. The plasma concentrations of ENR and its metabolite ciprofloxacin (CIP) were measured by liquid chromatography tandem–mass spectrometry. The concentrations of ENR and CIP in the plasma were quantified up to 144 hr after both the administrations. The half-life was long (43–44 hr) and similar after both administrations. The absolute i.m. bioavailability was 82.65% and the binding percentage of ENR to plasma protein ranged from 9% to 18% with an average of 10.6%. Percentage of CIP (plasma concentrations) was 15.9% and 19.9% after i.v. and i.m. administration, respectively. Based on the pharmacokinetic data, susceptibility break point and PK-PD indexes, i.m. single administration of ENR at a dosage of 5 mg/kg b.w. might be appropriate for treatment of susceptible bacteria (MIC > 1 μg/mL) in freshwater crocodiles, C. siamensis.     

Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses

The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control. Blood samples were collected up to 72 hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine‐3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine‐6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4 ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady‐state and systemic clearance ranged from 9.40 to 16.9 L/kg and 23.3 to 32.4 ml min^?1 kg^?1, respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites.     

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

OBJECTIVE: To determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 microg kg(-1)) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 microg kg(-1) hour(-1) lasting 1, 3 or 4 hours in dogs. Animals Fourteen healthy adult beagles (seven males and seven females). EXPERIMENTAL DESIGN: Randomized cross-over design. MATERIALS AND METHODS: Dogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 microg kg(-1)). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 microg kg(-1) hour(-1)) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography-mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). RESULTS: Plasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration-time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2alpha was 4.5 minutes), a relatively long elimination half time (t1/2beta was 45.7 minutes), a large volume of distribution (approximately 5 L kg(-1)) and high total body clearance (77.9 mL minute(-1) kg(-1)). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. CONCLUSIONS AND CLINICAL RELEVANCE: While this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.