Effects of housing environment on oral absorption of acetaminophen in healthy Beagles

Melanie Madsen Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Hiroko Enomoto Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Kristen Messenger Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Mark G. Papich Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Abstract

OBJECTIVE

To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs.

ANIMALS

6 healthy Beagles.

PROCEDURES

Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography.

RESULTS

A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments.

CLINICAL RELEVANCE

Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Abstract

OBJECTIVE

To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs.

ANIMALS

6 healthy Beagles.

PROCEDURES

Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography.

RESULTS

A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments.

CLINICAL RELEVANCE

Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Introduction

Acetaminophen has historically been used as a marker drug for evaluation of gastrointestinal absorption.16 Because the rate of drug absorption is dependent on the rate at which the stomach delivers the drug to the small intestine, the rate of absorption reflects the gastric emptying time. The motility of the gastrointestinal tract is directly influenced by the autonomic nervous system.7 In times of stress, the sympathetic nervous system may override or diminish parasympathetic tone and inhibit motility and secretion of the gastrointestinal tract.8

Dogs confined in cages in a hospital environment have significantly different gastric emptying times, compared with dogs in their normal home environment.911 These investigators concluded that hospitalization of dogs may result in prolonged gastric emptying times, which could adversely affect gastric emptying of meals, gastrointestinal transit of orally administered drugs, and assessments of motility disorders. Stress induced in Beagles impedes gastric emptying rate measured with a radionuclide tracer as a result of deceased antral motor activity, but does not significantly affect emptying of the fundus into the distal portion of the stomach.12 Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone concentrations have also been reported in dogs.13 In the dogs in that study, stress induced a significant lengthening of the gastric and jejunal postprandial patterns and slowing of gastric emptying.

The objective of the study reported here was to assess the effect of a stress environment on gastric emptying in dogs, with oral absorption of acetaminophen used as a marker for gastric emptying. To accomplish our objective, we performed a crossover study to compare the oral absorption of acetaminophen in dogs while they were housed in 2 different environments (their normal environment or a cage in an unfamiliar environment). A secondary objective was to correlate acetaminophen absorption with gastrointestinal motility by use of a telemetric motility capsule, as described by Koziolek et al.14 In a previous study,1 systemic absorption of acetaminophen from the intestine was associated with gastric emptying time in dogs.

Materials and Methods

Animals

Six healthy research Beagles from the North Carolina State University College of Veterinary Medicine Laboratory Animal Resources were used in the study. Mean weight at the time of the study was 10.6 kg (SD, 1.19 kg), and dogs were all 4 years of age. All dogs were deemed healthy on the basis of results of physical examination. The dogs were housed in the college’s Laboratory Animal Facilities throughout the study and maintained on their regular diet. The Laboratory Animal Resources facility is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International and complies with the animal care regulations of the Animal Welfare Act and the Public Health Service Policy on Humane Care and Use of Laboratory Animals. All drug administration and sample collection were supervised by board-certified veterinarians. The study was approved by the college’s Institutional Animal Care and Use Committee prior to the start of the project (Approval No. 20-232).

Procedures

A crossover study design was used, through which all dogs were administered an oral acetaminophen tablet while housed in their normal housing environment (phase 1) and were then administered an oral acetaminophen tablet while housed in an unfamiliar, caged environment (phase 2). During phase 1, dogs were kept in individual runs measuring 105.6 X 105.6 cm, which was a familiar environment to which they had been acclimated and where they had been kept for several months. After dogs completed phase 1 of the study, a 7-day washout period was allowed, and phase 2 was completed. During phase 2, dogs were confined in a small, unfamiliar room in individual stainless steel cages measuring 61.6 X 60.5 X 60.5 cm that allowed for only restricted movements and were let out of the cages only briefly while the cages were being cleaned. On the morning the dogs were moved to the unfamiliar, caged environment, they were administered the same dose of acetaminophen.

Dogs received a single, intact, 325-mg acetaminophen tablet (Tylenol oral tablet); mean dose was 31.1 mg/kg (SD, 3.80 mg/kg). Each acetaminophen dose was followed by 35 mL of water to ensure passage down the esophagus. A volume of 35 mL was selected to comply with the volume used to evaluate the biopharmaceutical classification system for oral tablets in dogs.15 Each dog was also given a telemetric motility capsule (Smart Pill Motility Testing System; Medtronic), as described by Koziolek et al,14 to evaluate gastrointestinal motility. Food was withheld for approximately 18 hours prior to tablet administration, and feeding was resumed 4 hours after tablet administration.

On the day prior to drug administration, 20-gauge, 8-cm jugular IV catheters were inserted to facilitate blood collection. Dogs were mildly sedated with dexmedetomidine hydrochloride (10 µg/kg, IM) to decrease movement during catheter insertion. After catheter placement, sedation was reversed by administration of an equivalent volume of atipamezole. Each dog was allowed a recovery time of 24 hours prior to oral administration of acetaminophen. Blood samples were collected into evacuated tubes containing lithium heparin at 0 (prior to acetaminophen administration), 10, 20, and 40 minutes and 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours. Blood samples were kept on the ice and centrifuged at 3,500 X g for 10 minutes within 1 hour of collection. Plasma samples were stored in –80 °C until analysis, and all samples were analyzed within 3 weeks after collection. Rectal clearance of the telemetric motility capsule was confirmed by periodic visual inspection of each dog’s feces. During all procedures, dogs were observed for adverse effects associated with drug administration by licensed and board-certified veterinarians.

Plasma drug analysis

Plasma acetaminophen concentrations were determined by means of high-pressure liquid chromatography (HPLC).16 The HPLC system (1200 series system; Agilent Technologies) consisted of a quaternary solvent delivery system with a flow rate of 1.0 mL/min, autosampler, and UV detector set at a wavelength of 254 nm. Chromatograms were integrated with the HPLC software (OpenLAB; Agilent Technologies). A C18 column (Zorbax XDB Eclipse C18, 4.6 X 15-cm column; Agilent Technologies) was used and maintained at a constant temperature (35 °C). The mobile phase consisted of 92% distilled water and 8% acetonitrile. A 0.1% trifluoroacetic acid solution was added to the mobile phase as a pH modifier. An acetaminophen analytical reference standard (Sigma-Aldrich Corp) was used to prepare a stock solution in methanol, which was used to fortify blank plasma harvested from blood samples collected from the dogs prior to treatment (control plasma). The stock solution was sealed and stored in the dark in a refrigerator. The calibration curve for acetaminophen consisted of 7 standard solutions with concentrations that ranged from 0.05 to 50 μg/mL and included a blank (0 μg/mL) sample. The blank sample was used to detect interfering peaks that eluted into the window of the chromatographic peak of interest and to measure background interference. The calibration curve was accepted if the linear coefficient of determination (R2) was ≥ 0.99 and the calibration curve concentrations could be back calculated to within ≤ 15% of the true concentrations of the standard solutions.

All plasma, calibration, quality control, and blank plasma samples were prepared in an identical manner. Four hundred microliters of each plasma sample was added to a conditioned solid-phase extraction cartridge (Oasis HLB 1-mL solid phase extraction cartridge; Waters Corp). The sample from the cartridge was collected into a clean glass tube by elution with 1 mL of 100% methanol. The eluted samples were evaporated to yield a dry residue by heating the tubes at 40 °C under airflow. The residue in each tube was reconstituted by addition of 200 μL of the mobile phase; the solution was briefly vortexed and then transferred to an HPLC injection vial. A 30-μL aliquot of each sample was used for injection into the HPLC system. Retention time for the peak of interest was approximately 4.3 minutes. Fresh calibration and blank samples were prepared for analysis each day. The limit of quantification for acetaminophen in canine plasma was 0.05 μg/mL, which was determined from the lowest point on a linear calibration curve that yielded acceptable accuracy. The limit of detection was 0.01 µg/mL, which was determined on the basis of the signal-to-noise ratio. Laboratory procedures were conducted in accordance with published guidelines.17

Pharmacokinetic analysis

Plasma acetaminophen concentrations were plotted for visual assessment of the best model for pharmacokinetic analysis. Analysis of plots and pharmacokinetic modeling were performed with computer software (Phoenix WinNonlin; Certara), and 1-, 2-, and 3-compartment models were fit to the data. After examination of the diagnostic plots, residual plots, and Akaike information criterion,18 a 2-compartment model with lag-time (tlag) input was selected for the oral dosing data according to the following equation:
article image
where C(t) was the plasma drug concentration at time t; A and B were the y-axis intercepts for the distribution and elimination phases of the plasma concentration-versus-time curve, respectively; and α, β, and k01 were the distribution, elimination, and absorption rates, respectively. Half-lives were calculated from α and β values. Lag time accounted for the delay in appearance of acetaminophen in the blood after oral administration of the tablet. Other compartmental pharmacokinetic parameters were calculated according to formulae described by the software. A weighting factor of 1/y2 was applied to the data for model fitting. Values below the limit of quantification but above the limit of detection were included in the analysis and not weighted differently from other values because reporting such numbers as 0 would have impacted the results of the model and caused possible bias.19

Statistics analysis

All data were tested for normality with the Shapiro-Wilk test. Pharmacokinetic variables that were not normally distributed were compared between housing environments with the Wilcoxon matched-pairs signed rank test. Pharmacokinetic variables that were normally distributed were compared between housing environments with the paired t test. All analyses were conducted with standard statistical software (Prism software 7.04; GraphPad). Values of P < 0.05 were considered significant.

Results

No adverse effects were observed in association with administration of the oral acetaminophen tablets or telemetric motility capsules. All dogs completed both phases of the study without any observed problems.

Plasma acetaminophen concentrations and pharmacokinetics

Mean plasma acetaminophen concentrations after drug administration for the 2 housing environments are graphically displayed (Figure 1). A 2-compartment model with tlag was the best fit for both phases of the study (Figure 2). None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments (Table 1).

Figure 1
Figure 1

Mean plasma acetaminophen concentrations in 6 healthy Beagles after oral administration of a single 325-mg acetaminophen tablet (mean dose, 31.1 mg/kg; SD, 3.80 mg/kg) in a crossover study with the dogs housed in their normal environment (squares) or in a cage in an unfamiliar environment (circles). Error bars represent SD; notice that the y-axis scale is logarithmic.

Citation: American Journal of Veterinary Research 83, 1; 10.2460/ajvr.21.06.0075

Figure 2
Figure 2
Figure 2

Individual plasma acetaminophen concentrations for the dogs in Figure 1 with the dogs housed in their normal environment (A) or in a cage in an unfamiliar environment (B). In each graph, the solid line represents the geometric mean concentration-versus-time curve.

Citation: American Journal of Veterinary Research 83, 1; 10.2460/ajvr.21.06.0075

Table 1

Pharmacokinetic parameters calculated from plasma acetaminophen concentrations for 6 healthy Beagles after oral administration of a single 325-mg acetaminophen tablet (mean dose, 31.1 mg/kg; SD, 3.80 mg/kg) in a crossover study with the dogs housed in their normal environment or in a cage in an unfamiliar environment.

Parameter Normal housing Unfamiliar housing
Geometric mean CV (%) Minimum Maximum Geometric mean CV (%) Minimum Maximum
AUC (h•µg/mL) 26.56 23.96 20.08 37.80 27.31 31.16 17.11 37.38
α (1/h) 1.38 18.76 1.01 1.79 1.29 16.36 1.05 1.52
β (1/h) 0.18 38.66 0.12 0.35 0.18 50.11 0.13 0.45
t1/2β (h) 3.95 38.66 1.97 5.61 3.81 50.11 1.53 5.40
Cmax (µg/mL) 20.65 33.94 11.82 29.26 22.82 26.05 17.33 32.84
k01 (1/h) 5.62 112.33 1.70 13.96 8.75 120.01 2.54 24.55
k01 t1/2 (h) 0.12 112.33 0.05 0.41 0.08 120.01 0.03 0.27
k10 (1/h) 1.30 18.21 0.96 1.69 1.22 14.80 1.01 1.43
k12 (1/h) 0.06 41.45 0.04 0.09 0.05 44.68 0.03 0.11
k21 (1/h) 0.18 39.95 0.13 0.38 0.19 53.57 0.13 0.51
tmax (h) 0.64 38.09 0.43 1.16 0.61 56.38 0.42 1.71

A 2-compartment model with lag time (tlag) was the best fit for both phases of the study.

α = Rate constant for the distribution phase. AUC = Area under the concentration-versus-time curve. β = Rate constant for the elimination phase. Cmax = Maximum plasma concentration. k01 = Rate constant for absorption into the central compartment. k01 t1/2 = Half-life of absorption into the central compartment. k10 = Rate constant for drug elimination from the central compartment. k12 = Rate constant for drug movement from compartment 1 to compartment 2. k21 = Rate constant for drug movement from compartment 2 to compartment 1. t1/2β = Elimination half-life. tmax = Time to maximum plasma concentration.

Results from the telemetric motility capsule are not shown because capsules were retained in the dogs’ stomachs for excessively long times. Mean gastric emptying time was approximately 26.8 hours, and mean time until passage in the feces was 49.6 hours.

Discussion

Results of the present study suggested that stress induced by altering the housing environment of healthy Beagles did not significantly affect the oral absorption of acetaminophen. In addition, because acetaminophen absorption is reportedly a reliable marker of gastric emptying time in dogs,16 our findings suggested that altering the housing environment did not affect gastric emptying of acetaminophen.

In developing our study, we hypothesized that moving dogs to an unfamiliar, caged environment would constitute a stressful event similar to housing patients in a hospital setting and would, thus, affect gastric emptying and motility. Our results were different from those of a previous study9 that analyzed gastric emptying with a wireless motility capsule. In that study, there was a significant difference in gastric emptying between dogs that were hospitalized versus at home in their normal environment, but there was no observed difference in other measured values such as small and large intestinal motility, transit time, and pH. Other investigators also have reported that induced stress in dogs significantly affects gastric emptying time, most likely by interfering with neural pathways stemming from the CNS and altering hormone concentrations. For example, inducing acoustic stress (80- to 90-dB broad range frequency) for 2 hours after feeding led to decreased gastric emptying of both the liquid and solid components of a radiolabeled meal.13 Specifically, those investigators found that acoustic stress slowed gastric emptying within the first 30 minutes after consumption of a meal, but that by 2 hours after meal consumption, gastric emptying was similar to that of a control group that did not undergo acoustic stress.13 In another study,12 transporting a dog to an unfamiliar environment induced stress and caused a decrease in gastric emptying by impairing antral motility. In that study, however, emptying of the fundic portion of the stomach was not altered when radiolabeled contents of a solid meal were followed with a γ camera.12

In the present study, it is possible that changing the dogs’ housing environment from their familiar runs in our research facility to smaller cages in a confined space did not induce sufficient stress to induce an effect. We did not measure biomarkers of induced stress in dogs, such as cortisol concentrations or plasma gut hormone concentrations,13 to identify differences between housing environments in these dogs. Dogs used in our study were also healthy, so we cannot conclude whether sick hospitalized dogs will respond in a similar way. Without other corroborating data, such as from a telemetric motility capsule, analysis of acetaminophen absorption may not be a sensitive enough measure of gastric emptying in healthy dogs.

One of our objectives was to correlate stomach emptying of acetaminophen with gastric emptying time measured with a telemetric motility capsule. However, we judged our results to be excessively long, compared with results of previous studies,1,14,15 and not representative of the true gastric emptying time in these dogs. Delayed gastric emptying of the capsule may have been a result of the large size of the telemetric motility capsule (13 X 27 mm) we used. These capsules were designed for use in studies of people, and our dogs had a mean weight of 10.6 kg. Small dogs may have more difficulties passing this large capsule than do larger dogs, and a similar effect was observed in a previous study,20 with the authors of that study warning that “due to its large size, the wireless motility capsule should not be used in smaller dogs.” In another study,21 the authors used the same wireless motility capsule as we used in our study and reported gastric emptying times ranging from 385 to 670 minutes, even though mean weight of their dogs was 21.5 kg. These authors21 concluded that use of this capsule to monitor gastric emptying times should be limited to dogs weighing ≥ 15 kg. In a study22 in which video capsule endoscopy was used in dogs, the authors reported that the capsules were retained in the stomach for > 6 hours in 39% of the dogs, resulting in an incomplete study.

The stomach in dogs is more restrictive to emptying than the stomach in humans, and in dogs, particles do not pass freely from the stomach to the duodenum unless they are < 2 to 3 mm in size. Particles > 5 mm will typically have to wait for a housekeeper wave to be propelled through the pylorus into the duodenum. In contrast, people can typically pass particles through the pylorus that are up to 17.6 mm in diameter.15 Comparison of our results with those for larger dogs is needed to confirm our speculation that gastric emptying time in our study was reflective of the small size of the dogs we used.

The pharmacokinetics of acetaminophen following oral administration in the present study were different from those published previously2326 (Table 2). Our study used Beagles, whereas previous studies used mixed-breed dogs, Greyhounds, or Labrador Retrievers, which could account for the differences noted, especially in that other studies27,28 have identified pharmacologic and metabolic differences among dog breeds. For example, Greyhounds are known to have a reduced capacity to eliminate various anesthetic drugs, and clearance has also been shown to be slower in Greyhounds than in Beagles, with mixed-breed dogs having clearances that span the values for these 2 breeds.29 Also, several previous studies used noncompartmental pharmacokinetic analysis. With noncompartmental modeling, maximum plasma concentration and time to maximum plasma concentration are determined directly from the observed concentration-versus-time curve, whereas with compartmental modeling, these values are calculated on the basis of predicted concentrations for the sampling times.

Table 2

Comparison of pharmacokinetic parameters for oral acetaminophen administration in the present study and in previously published studies.

Variable Present study Savides et al23 Kukanich24 Sikina et al25 Sartini et al26
Mean dose (mg/kg) 31.1 100 7.6–10.9 9.3–13.3 20
Breed Beagle Mixed Greyhound Mixed Labrador Retriever
Model CA CA NCA NCA NCA
AUC (h•µg/mL) 26.5 NR 13.8 7.8 40.4
t1/2β (h) 4.0 1.2 NR NR NR
Cmax (µg/mL) 20.7 48 6.7 2.7 9.3
tmax (h) 0.62 2.0 0.85 1.0 2.0

CA = Compartmental analysis. NCA = Noncompartmental analysis. NR = Not reported.

See Table 1 for remainder of key.

The present study was not designed to determine whether acetaminophen administration in these dogs resulted in any degree of analgesia. However, plasma concentrations greater than the therapeutic threshold concentration of 4 µg/mL proposed in a previous study26 were maintained for only 2 hours after administration in our study, even though we used a higher dose. Therefore, dose intervals of ≥ 8 hours would not consistently result in plasma concentrations above the proposed therapeutic range in these dogs.

In conclusion, oral administration of acetaminophen (mean dose, 31.1 mg/kg; SD, 3.80 mg/kg) as a marker for gastric emptying in 6 healthy Beagles did not reveal any significant differences when the dogs were housed in their normal environment versus an unfamiliar, caged environment. Further studies involving larger dogs may be warranted to determine whether the telemetric motility capsule we used in the present study can successfully provide gastric emptying times that match those obtained with acetaminophen as a biomarker. In addition, studies are needed assessing the effects of stress on gastric emptying times in fed versus fasted dogs.

Acknowledgments

Funded in part by a grant from the North Carolina State University College of Veterinary Medicine Department of Molecular Biomedical Sciences. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

The authors declare that there were no conflicts of interest.

The authors thank Delta R. Dise of the North Carolina State University Clinical Pharmacology Laboratory for assistance performing drug assays and thank Lauren Buslinger of the North Carolina State University Central Procedures Laboratory for technical assistance.

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  • Figure 1

    Mean plasma acetaminophen concentrations in 6 healthy Beagles after oral administration of a single 325-mg acetaminophen tablet (mean dose, 31.1 mg/kg; SD, 3.80 mg/kg) in a crossover study with the dogs housed in their normal environment (squares) or in a cage in an unfamiliar environment (circles). Error bars represent SD; notice that the y-axis scale is logarithmic.

  • Figure 2

    Individual plasma acetaminophen concentrations for the dogs in Figure 1 with the dogs housed in their normal environment (A) or in a cage in an unfamiliar environment (B). In each graph, the solid line represents the geometric mean concentration-versus-time curve.

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