The effect of sucralfate tablets vs. suspension on oral doxycycline absorption in dogs

The purpose of this study was to determine the effect of concurrent sucralfate (tablet or suspension) on doxycycline pharmacokinetics and to determine the effects of delaying sucralfate by 2 h on doxycycline absorption. Five dogs were included in a crossover study receiving: doxycycline alone; doxycycline concurrently with sucralfate tablet; doxycycline followed 2 h by sucralfate tablet; doxycycline concurrently with sucralfate suspension; and doxycycline followed 2 h by sucralfate suspension. Doxycycline plasma concentrations were evaluated with liquid chromatography with mass spectrometry. No interaction was seen when sucralfate was administered as a tablet. Sucralfate tablet fragments were frequently observed in some dogs' feces. The area under the curve (AUC) and maximum plasma concentration (C_MAX) were significantly lower (P < 0.001) in the concurrent sucralfate suspension group (AUC 7.2 h·μg/mL, C_MAX 0.43 μg/mL) than with doxycycline alone (AUC 36.0 h·μg/mL, C_MAX 2.53 μg/mL) resulting in a relative bioavailability of 20%. Delaying sucralfate suspension by 2 h after doxycycline administration resulted in no difference in doxycycline absorption as compared with doxycycline administration alone with a relative bioavailability of 74%. The lack of an interaction with sucralfate tablets suggests sucralfate should be administered as a suspension rather than tablet in dogs.     

Effect of morphine on the bispectral index during isoflurane anesthesia in dogs

ObjectiveTo assess the effect of morphine on the bispectral index (BIS) in dogs during isoflurane anesthesia maintained at a constant end–tidal concentration.Study designProspective, randomized, experimental trial.AnimalsEight adult Beagle dogs, weighing between 7.1 and 9.8 kg.MethodsAnesthesia was induced with isoflurane via a face mask. Dog's tracheas were intubated and anesthesia maintained with isoflurane at a constant end–tidal concentration (e′Iso) of 1.81% for a 30–minute equilibration period. Pulmonary ventilation was controlled to normocapnia. After equilibration, baseline values were recorded prior to intravenous administration of morphine sulfate (0.5 mg kg^?1) (MT) or an equal volume of saline (CT). Measurements for heart rate, systolic, diastolic and mean arterial pressure (SAP, DAP and MAP) were recorded at 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after treatment. Bispectral index was recorded every 10 seconds for 3 minutes for each time measurement. Venous blood samples were collected at baseline, 10, 20, 30, 45, 60 and 120 minutes for determination of morphine serum concentrations. Anesthesia was discontinued after the last measurement and dogs were allowed to recover.ResultsBaseline BIS for MT and CT at 1.81%e′Iso were 63 ± 10 and 58 ± 9, respectively. Bispectral index in MT was 4–8% lower at 20, 75, 90 and 105 minutes compared with CT. There were no differences in BIS between baseline and any subsequent measurement within either MT or CT. Heart rate, SAP, MAP, and DAP decreased after morphine administration.Conclusion and clinical relevanceIntravenous administration of 0.5 mg kg^?1 morphine sulfate did not cause clinically significant changes in the BIS of unstimulated dogs during isoflurane anesthesia at an e′Iso of 1.81%.     

The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna? was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R ² > 0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24‐hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed‐specific parameters.     

Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs

To determine the plasma pharmacokinetics of suppository acetaminophen (APAP) in healthy dogs and clinically ill dogs. This prospective study used six healthy client‐owned and 20 clinically ill hospitalized dogs. The healthy dogs were randomized by coin flip to receive APAP orally or as a suppository in crossover study design. Blood samples were collected up to 10 hr after APAP dosing. The hospitalized dogs were administered APAP as a suppository, and blood collected at 2 and 6 hr after dosing. Plasma samples were analyzed by ultra‐performance liquid chromatography with triple quadrupole mass spectrometry. In healthy dogs, oral APAP maximal concentration (C_MAX=2.69 μg/ml) was reached quickly (T_MAX=1.04 hr) and eliminated rapidly (T1/2 = 1.81 hr). Suppository APAP was rapidly, but variably absorbed (C_MAX=0.52 μg/ml T_MAX=0.67 hr) and eliminated (T_1/2 = 3.21 hr). The relative (to oral) fraction of the suppository dose absorbed was 30% (range <1%–67%). In hospitalized ill dogs, the suppository APAP mean plasma concentration at 2 hr and 6 hr was 1.317 μg/ml and 0.283 μg/ml. Nonlinear mixed‐effects modeling did not identify significant covariates affecting variability and was similar to noncompartmental results. Results supported that oral and suppository acetaminophen in healthy and clinical dogs did not reach or sustain concentrations associated with efficacy. Further studies performed on different doses are needed.     

Comparative disposition of pharmacologic markers for cytochrome P-450 mediated metabolism, glomerular filtration rate, and extracellular and total body fluid volume of Greyhound and Beagle dogs

The purpose of the study was to compare the disposition of pharmacologic markers for cytochrome P-450 (CYP) metabolism, glomerular filtration rate (GFR), and extracellular (ECFV) and total body fluid volumes (TBFV) of Greyhounds and Beagles. Six healthy Greyhound and six healthy Beagle dogs were studied. Antipyrine, a marker for CYP metabolism and TBFV, and inulin, a marker for the GFR and ECFV, were administered i.v. Samples were collected at predetermined times and plasma was analyzed by validated high-pressure liquid chromatography (HPLC) methods. There were no differences in the disposition or pharmacokinetic parameters for inulin between the dog breeds. However, the clearance of antipyrine (mean = 8.33 mL/min/kg) in Greyhounds was significantly slower than Beagles (13.42 mL/min/kg, P = 0.004). The volume of distribution of antipyrine was significantly larger in Greyhounds (0.789 L/kg) than in Beagles (0.644 L/kg, P = 0.01). The half-life of antipyrine was significantly longer in Greyhounds (1.09 h) compared with Beagles (0.55 h, P = 0.002). The in vitro plasma protein binding of antipyrine was significantly less in Greyhounds (28%) compared with Beagles (40.3%, P = 0.008). Greyhounds exhibited significantly slower CYP metabolism, higher TBFV, and lower in vitro protein binding of antipyrine compared with Beagles. No differences in GFR or ECFV were found.     

Pharmacokinetics of oral meloxicam in ruminant and preruminant calves

The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster (P<0.01) in PRF (0.237±0.0478/h) than RG calves (0.0815±0.0188/h), while absorption in PRG calves (0.153±0.128/h) was not different from other groups. C(max) was lower (P=0.03) in PRF (1.27±0.430 μg/mL) than in PRG calves (2.20±0.467 μg/mL), while C(max) of RG calves (1.95±0.955 μg/mL) was not different from other groups. V/F was higher in PRF calves (365±57 mL/kg) than either PRG (177±63 mL/kg, P<0.01) or RG (232±83 mL/kg, P=0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer.     

Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs

Tramadol is an analgesic and antitussive agent that is metabolized to O-desmethyltramadol (M1), which is also active. Tramadol and M1 exert their mode of action through complex interactions between opiate, adrenergic, and serotonin receptors. The pharmacokinetics of tramadol and M1 were examined following intravenous and oral tramadol administration to six healthy dogs, as well as intravenous M1 to three healthy dogs. The calculated parameters for half-life, volume of distribution, and total body clearance were 0.80 +/- 0.12 h, 3.79 +/- 0.93 L/kg, and 54.63 +/- 8.19 mL/kg/min following 4.4 mg/kg tramadol HCl administered intravenously. The systemic availability was 65 +/- 38% and half-life 1.71 +/- 0.12 h following tramadol 11 mg/kg p.o. M1 had a half-life of 1.69 +/- 0.45 and 2.18 +/- 0.55 h following intravenous and oral administration of tramadol. Following intravenous M1 administration the half-life, volume of distribution, and clearance of M1 were 0.94 +/- 0.09 h, 2.80 +/- 0.15 L/kg, and 34.93 +/- 5.53 mL/kg/min respectively. Simulated oral dosing regimens at 5 mg/kg every 6 h and 2.5 mg/kg every 4 h predict tramadol and M1 plasma concentrations consistent with analgesia in humans; however, studies are needed to establish the safety and efficacy of these doses.     

Analysis of weight uniformity, content uniformity and 30-day stability in halves and quarters of routinely prescribed cardiovascular medications

Objectives

Congenital and acquired cardiac disorders are frequently diagnosed in small breed dogs and cats. In order to appropriately dose cardiovascular drugs for small patients, fractions of commercially available tablets must be prescribed. The aims of this study were to evaluate weight and content uniformity and 30-day chemical stability in halves and quarters of 11 drug formulations commonly prescribed to treat cardiovascular disorders in small breed dogs and cats.

Animals, materials and methods

Fifteen tablets from 11 drug formulations were obtained within the same lot. Tablets were split by a single operator using a commercially available pill splitter. Whole tablets, halves and quarters were weighed and stored in plastic containers. High-pressure liquid chromatography or liquid chromatography with mass spectrometry were utilized to determine drug content and repeated 30 days later to estimate chemical stability.

Results

Statistically significant weight variability, content non-uniformity and chemical degradation were found for some formulations. Digoxin showed a significant degradation that should be considered in clinical practice.

Conclusions

It appears that pill splitting is overall a relatively reliable practice; however tablets should not be split ahead of time but only immediately prior to intended usage.