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.     

The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.     

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%.     

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.     

Pharmacokinetics of oral terbinafine in adult horses

The primary study objective was to compare the pharmacokinetics of p.o. terbinafine alone to p.o. terbinafine administered with p.o. cimetidine in healthy adult horses. The second objective was to assess the pharmacokinetics of terbinafine when administered per rectum in two different suspensions at 30 mg/kg to adult horses. Six healthy adult horses were included in this crossover study. Plasma terbinafine concentrations were quantified with liquid chromatography and mass spectrometry. The half‐life (geometric mean) was 8.38 and 10.76 h, for p.o. alone and p.o. with cimetidine, respectively. The mean maximum plasma concentrations were 0.291 μg/mL at 1.54 h and 0.418 μg/mL at 1.28 h for p.o. alone and p.o. with cimetidine, respectively. Terbinafine with cimetidine had an average C_MAX 44% higher and the relative F was 153% compared p.o. terbinafine alone, but was not statistically different (P > 0.05). Terbinafine was infrequently detected when administered per rectum in two different suspensions (water or olive oil). Minor adverse effects included oral irritation, fever, and colic. All resolved spontaneously. More pharmacokinetic studies are indicated assessing drug–drug interactions and using multiple dosing intervals to improve our knowledge of effective oral dosing, the potential for drug accumulation, and systemic adverse effect of terbinafine in horses.     

The disposition and behavioral effects of methadone in Greyhounds

ObjectiveTo determine the behavioral effects and pharmacokinetics of methadone in healthy Greyhounds.Study designProspective experimental study.AnimalsThree male and three female healthy Greyhounds.MethodsMethadone hydrochloride, 0.5 mg kg⁻¹ IV (equivalent to 0.45 mg kg⁻¹ methadone base), was administered as an IV bolus. Trained observers subjectively assessed the behavioral effects of methadone. Blood samples were obtained at predetermined time points and plasma methadone concentrations were measured by liquid chromatography with tandem mass spectrometry. Pharmacokinetic variables were estimated with computer software.ResultsMethadone was well tolerated by the dogs with panting and defecation observed as adverse effects. Mild sedation was present, but no vomiting, excitement, or dysphoria was observed. The elimination half-life, volume of distribution, and plasma clearance were 1.53 ± 0.18 hours, 7.79 ± 1.87 L kg⁻¹, and 56.04 ± 9.36 mL minute⁻¹ kg⁻¹, respectively.Conclusions and clinical relevanceMethadone was well tolerated by Greyhounds. The volume of distribution was larger than expected, with resultant lower plasma concentrations than expected. Higher doses may need to be administered to Greyhounds in comparison with non-Greyhound dogs in order to achieve similar plasma drug concentrations. A dosage of 1–1.5 mg kg⁻¹ every 3–4 hours is suggested for future studies of analgesic efficacy of methadone in Greyhounds.     

The disposition of lidocaine during a 12-hour intravenous infusion to postoperative horses

Lidocaine is administered as an intravenous infusion to horses for a variety of reasons, but no study has assessed plasma lidocaine concentrations during a 12-h infusion to horses. The purpose of this study was to evaluate the plasma concentrations and pharmacokinetics of lidocaine during a 12-h infusion to postoperative horses. A second purpose of the study was to evaluate the in vitro plasma protein binding of lidocaine in equine plasma. Lidocaine hydrochloride was administered as a loading dose, 1.3 mg/kg over 15 min, then by a constant rate IV infusion, 50 microg/kg/min to six postoperative horses. Lidocaine plasma concentrations were measured by a validated high-pressure liquid chromatography method. One horse experienced tremors and collapsed 5.5 h into the study. The range of plasma concentrations during the infusion was 1.21-3.13 microg/mL. Lidocaine plasma concentrations were significantly increased at 0.5, 4, 6, 8, 10 and 12 h compared with 1, 2 and 3 h. The in vitro protein binding of lidocaine in equine plasma at 2 microg/mL was 53.06+/-10.28% and decreased to 27.33+/-9.72% and 29.52+/-6.44% when in combination with ceftiofur or the combination of ceftiofur and flunixin, respectively. In conclusion, a lower lidocaine infusion rate may need to be administered to horses on long-term lidocaine infusions. The in vitro protein binding of lidocaine is moderate in equine plasma, but highly protein bound drugs may displace lidocaine increasing unbound concentrations and the risk of lidocaine toxicity.