Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs

Pharmacokinetic analysis of buprenorphine administered to six healthy dogs via the oral transmucosal (OTM) route at doses of 20 and 120 microg/kg was conducted using liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC-ESI-MS/MS). Bioavailability was 38% plus or minus 12% for the 20 microg/kg dose and 47%+/-16% for the 120 microg/kg dose. Maximum plasma concentrations were similar for buprenorphine doses of 20 microg/kg IV and 120 microg/kg OTM. Sedation and salivation were common side effects, but no bradycardia, apnea, or cardiorespiratory depressive effects were seen. When the two OTM dosing rates were normalized to dose, LC-ESI-MS/MS analysis of buprenorphine and its metabolites detected no significant difference (P>.05), indicating dose proportionality. The results of this study suggest that OTM buprenorphine may be an alternative for pain management in dogs.     

Pharmacokinetics of buprenorphine following intravenous administration in dogs

OBJECTIVE: To determine pharmacokinetics of buprenorphine in dogs after i.v. administration. ANIMALS: 6 healthy adult dogs. PROCEDURES: 6 dogs received buprenorphine at 0.015 mg/kg, i.v. Blood samples were collected at time 0 prior to drug administration and at 2, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180, 240, 360, 540, 720, 1,080, and 1,440 minutes after drug administration. Serum buprenorphine concentrations were determined by use of double-antibody radioimmunoassay. Data were subjected to noncompartmental analysis with area under the time-concentration curve to infinity (AUC) and area under the first moment curve calculated to infinity by use of a log-linear trapezoidal model. Other kinetic variables included terminal rate constant (k(el)) and elimination half-life (t(1/2)), plasma clearance (Cl), volume of distribution at steady state (Vd(ss)), and mean residence time (MRT). Time to maximal concentration (T(max)) and maximal serum concentration (C(max)) were measured. RESULTS: Median (range) values for T(max) and MRT were 2 minutes (2 to 5 minutes) and 264 minutes (199 to 600 minutes), respectively. Harmonic mean and pseudo SD for t(1/2) were 270+/-130 minutes; mean +/- SD values for remaining pharmacokinetic variables were as follows: C(max), 14+/-2.6 ng/mL; AUC, 3,082+/-1,047 ng x min/mL; Vd(ss), 1.59+/-0.285 L/kg; Cl, 5.4+/-1.9 mL/min/kg; and, k(el), 0.0026+/-0.0,012. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetic variables of buprenorphine reported here differed from those previously reported for dogs. Wide variations in individual t(1/2) values suggested that dosing intervals be based on assessment of pain status rather than prescribed dosing intervals.     

Pharmacokinetics of buprenorphine after intravenous administration of clinical doses to dogs

The purpose of this study was to evaluate plasma concentrations and pharmacokinetic parameters of buprenorphine in dogs following intravenous (IV) administration of clinical doses of the opioid. An IV bolus of 0.02 mg/kg buprenorphine was administered to six healthy Beagles and blood samples were collected through a jugular catheter before and at 1, 5, 10, 15, 20, 30 and 45 min, and 1, 2, 4, 6, 8 and 12 h after administration. Plasma buprenorphine concentrations, measured using a commercial radioimmunoassay (RIA), decreased following a three-exponential curve. The two distribution and the elimination half-lives were 2.9 ± 1.8 min, 16.5 ± 3.7 min, and 266.6 ± 82.0 min, respectively; the clearance was 329.6 ± 62.2 mL/min, and the steady state volume of distribution was 83.7 ± 26.5 L.The results demonstrated the feasibility of the RIA assay to analyse buprenorphine in dog plasma samples. Following IV administration buprenorphine showed a three-compartment kinetic profile, as has been described previously in humans, rabbits and cats. The relationship between plasma concentrations and dynamic effects in dogs remains to be established.     

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.     

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 total thyroxine in dogs after administration of an oral solution of levothyroxine sodium

Oral l -thyroxine ( l -T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of l -T4 following administration of a solution (Leventa^®) was investigated in healthy dogs. l -T4 was absorbed fairly rapidly ( t _max 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 μg l -T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of l -T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with l -T4 oral administration delayed l -T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of l -T4 following administration of a tablet formulation was about 50% of that of the l -T4 solution. The pharmacokinetic properties of liquid l -T4 after oral administration support the use of a dose rate of 20 μg/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism.     

Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats

ObjectiveTo compare sedation and antinociception after oral transmucosal (OTM) and intramuscular (IM) administration of a dexmedetomidine-buprenorphine combination in healthy adult cats.Study designRandomized, ‘blinded’ crossover study, with 1 month washout between treatments.AnimalsSix healthy neutered female cats, weighing 5.3–7.5 kg.MethodsA combination of dexmedetomidine (40 μg kg^?1) and buprenorphine (20 μg kg^?1) was administered by either the OTM (buccal cavity) or IM (quadriceps muscle) route. Sedation was measured using a numerical rating scale, at baseline and at various time points until 6 hours after treatment. At the same time points, analgesia was scored using a dynamic and interactive visual analogue scale, based on the response to an ear pinch, and by the cat’s response to a mechanical stimulus exerted by a pressure rate onset device. Physiological and adverse effects were recorded, and oral pH measured. Signed rank tests were performed, with significance set at p < 0.05. Data are presented as median and range.ResultsThere were no differences in sedation or antinociception scores between OTM and IM dosing at any of the time points. Nociceptive thresholds increased after both treatments but without significant difference between groups. Buccal pH remained between 8 and 8.5. Salivation was noted after OTM administration (n = 2) and vomiting after both OTM (n = 4), and IM (n = 3) dosing.Conclusions and clinical relevanceIn healthy adult cats, OTM administration of dexmedetomidine and buprenorphine resulted in comparable levels of sedation and antinociception to IM dosing. The OTM administration may offer an alternative route to administer this sedative-analgesic combination in cats.     

PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration

The pharmacokinetics and thermal antinociceptive effects of buprenorphine after intravenous (i.v.) or oral transmucosal (OTM) administration were studied in six adult cats. Plasma buprenorphine concentrations were measured using radioimmunoassay in a crossover study after a dose of 20 microg/kg given by the i.v. or OTM route. Oral pH was measured. Blood for drug analyses was collected before, and at 1, 2, 4, 6, 10, 15, 30, and 60 min and at 2, 4, 6, 8, 12, and 24 h after treatment. Thermal thresholds were measured before treatment, then following treatment every 30 min to 6 h, every 1 hour to 12 h and at 24 hours postadministration. Plasma buprenorphine concentration effect relationships were analyzed using a log-linear effect model. Oral pH was 9 in each cat. Peak plasma buprenorphine concentration was lower and occurred later in the OTM group but median bioavailability was 116.3%. Thermal thresholds increased significantly between 30 and 360 min in both groups. Peak effect was at 90 min and there was no difference at any time between the two groups. There was distinct hysteresis between plasma drug concentration and effect in both groups. Overall, OTM administration of buprenorphine is as effective as i.v. treatment and offers a simple, noninvasive method of administration which produces thermal antinociception for up to 6 h in cats.     

Pharmacokinetics of sodium amoxicillin in foals after intramuscular administration

Pharmacokinetic values of sodium amoxicillin (22 mg/kg of body weight) in foals were determined after a single IM injection in 6 Quarter Horse foals at 3, 10, and 30 days of age. Serum amoxicillin concentrations were measured serially over a 24-hour period. The absorption of amoxicillin was rapid and followed a 1st-order elimination. Mean peak serum concentrations occurred 30 minutes after the injection in foals at all ages and were 17.31 +/- 9.59 micrograms/ml when the foals were 3 days old, 23.28 +/- 9.86 micrograms/ml when the foals were 10 days old, and 21.35 +/- 6.39 micrograms/ml when the foals were 30 days old. Serum samples collected beyond 8 hours after administration contained amoxicillin concentrations less than 0.05 micrograms/ml. The elimination rate constant increased with increasing age (0.5265 +/- 0.0891 hour-1 when the foals were 3 days old, 0.6494 +/- 0.1114 hour-1 when the foals were 10 days old, and 0.7112 +/- 0.1016 hour-1 when the foals were 30 days old). Serum clearance increased with increasing age (498.4 +/- 82.6 ml/hr/kg at 3 days, 631.6 +/- 170.5 ml/hr/kg at 10 days, and 691.2 +/- 127.3 ml/hr/kg at 30 days). Serum half-life decreased with increasing age (1.34 +/-0.243 hour at 3 days, 1.10 +/- 0.239 hour at 10 days, and 0.991 +/- 0.139 hour at 30 days), whereas the extrapolated concentration at time zero and apparent volume of distribution did not change during the first 30 days of age.     

Pharmacokinetics of kanamycin after subcutaneous and intravenous administration in dogs

Six beagle dogs were treated with kanamycin subcutaneously or intravenously in a dosage of 5 mg/kg. The plasma kanamycin concentration was measured over 24 hours by high pressure liquid chromatography with UV detection after derivatization and solid phase extraction. After subcutaneous application, kanamycin was absorbed quickly, and maximum plasma levels of 18.9 micrograms/ml in average after ca. 1 hour were measured. With complete systemic availability, the minimal inhibitory concentration of 4 micrograms/ml was maintained for 4 hours. After subcutaneous administration, kanamycin was terminally eliminated with a mean half life period of 2 hours.     

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 oestriol after repeated oral administration to dogs

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.     

Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration

Six dogs were treated with a single intravenous (i.v.) dose (2 mg/kg) of marbofloxacin, followed by single oral (p.o.) doses of marbofloxacin at 1, 2 and 4 mg/kg, according to a three-way crossover design. The same experimental design was used for the subcutaneous (s.c.) route. In addition, a long-term trial involving eight dogs given oral doses of marbofloxacin at 2, 4 and 6 mg/kg/day for thirteen weeks was carried out. Plasma and urine samples were collected during the first two trials, plasma and skin samples were collected after the second of these trials. Plasma, urine and skin concentrations of marbofloxacin were determined by a reverse phase liquid chromatographic method. Mean pharmacokinetic parameters after i.v. administration were the following: t1/2β=12.4h; Cl _B= 0.10 L/h.kg; V _area= 1.9 L/kg. The oral bioavailability of marbofloxacin was close to 100% for the three doses. At 2 mg/kg, C _max of 1.4 μg/mL was reached at t _max of 2.5 h. Mean AUC and C _max values had a statistically significant linear relationship with the doses administered. About 40% of the administered dose was excreted in urine as unchanged parent drug. After s.c. administration, the calculated parameters were close to those obtained after oral administration, except t _max (about 1 h) which was shorter. The mean skin to plasma concentration ratio after the long-term trial was 1.6, suggesting good tissue penetration of marbofloxacin.     

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment ( t _max = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed ( t _max = 2.25 h) and decreased the rate and extent of absorption ( AUC ) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.     

Pharmacokinetics of a high-concentration formulation of buprenorphine (Simbadol) in male dogs

ObjectiveTo describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine.Study designProspective, randomized, crossover study.AnimalsA total of six healthy male intact Beagle dogs, aged 9–13 months and weighing 10.3 ± 1.4 kg (mean ± standard deviation).MethodsDogs were randomized to be administered buprenorphine (0.12 mg kg^–1; Simbadol, 1.8 mg mL^–1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry.ResultsA three-compartment model with zero or biphasic rapid and slow first-order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first-order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg^–1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute^–1 kg^–1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minute delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239)%. Calculated terminal half-life was 963 minutes.Conclusions and clinical relevanceThe high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues.     

Pharmacokinetics of aditoprim in dogs after intravenous and oral administration: a preliminary study

The pharmacokinetics of aditoprim (2,4-diam-ino-5-[4-[dimethylamino]-3,5-dimethoxybenzyl] pyrimidine), a dihydrofolate reductase inhibitor, were studied in three eight to 17-month-old beagle dogs. The drug was alternately injected intravenously and administered orally as a tablet in two separate experiments. The doses ranged from 4–27 to 7–25 mg/kg bodyweight. The mean plasma clearance (CI) was 15-3 ml/min/kg and the mean volume of distribution (V_ss) 13-1 litres/kg. The mean plasma elimination half-life times after intravenous injection and oral administration were 11-6 and 9-6 hours, respectively. Aditoprim was readily (t_max= one to four hours) and completely absorbed from the intestinal tract (f = 89 per cent).