• View in gallery
    Figure 1—

    Lateral radiographic view of the abdomen of a lamb at the first stage (mean ± SD age, 10 ± 2 weeks) immediately after suckling a test solution containing acetaminophen and barium sulfate. Notice that the barium sulfate in the test solution is located in the abomasum and not in the reticulum, which indicates complete closure of the reticular groove.

  • View in gallery
    Figure 2—

    Lateral radiographic view of the abdomen of a lamb at the second stage (mean ± SD age, 16 ± 2 weeks) immediately after suckling a test solution. Notice that the barium sulfate in the test solution is located in the forestomachs, which indicates no or incomplete closure of the reticular groove.

  • View in gallery
    Figure 3—

    Plasma acetaminophen concentration over time for lambs when suckling a test solution (solid line) and when tube fed the test solution (dashed line) at stage 1 (A), stage 2 (B), and stage 3 (C) of the study. Notice that the scale on the y-axis differs among panels. The onset of administration of the test solution is indicated (arrow) and is designated as time 0. In all 3 panels, a proposed cutoff value of 25 μg/mL is indicated (horizontal dotted line). *Value for this time point differs significantly (P < 0.05) from the value for time 0. †Within a time point, values differ significantly (P < 0.05) between treatments.

  • View in gallery
    Figure 4—

    The ROC plots for Acet-T60 (solid line) and AUCAcet (dotted line) determined for 12 lambs at stage 1, 8 lambs at stage 2, and 12 lambs at stage 3. Sensitivity (horizontal dashed lines) and specificity (vertical dashed lines) were determined for suggested cutoff values of 24.9 μg/mL (point A) and 26.3 μg/mL (point B) for Acet-T60.

  • 1.

    Constable PD, Wittek T, Ahmed AF, et al. Abomasal pH and emptying rate in the calf and dairy cow and the effect of commonly administered therapeutic agents, in Proceedings. 24th World Buiatrics Cong 2006;5468.

    • Search Google Scholar
    • Export Citation
  • 2.

    Goff JP, Horst RL. Oral administration of calcium salts for treatment of hypocalcemia in cattle. J Dairy Sci 1993;76:101108.

  • 3.

    Scholz H. Utilization of the reticular groove contraction in adult cattle—a therapeutic alternative for the practitioner? Bovine Pract 1988;23:148152.

    • Search Google Scholar
    • Export Citation
  • 4.

    Orskov ER, Benzie D. Studies on the oesophageal groove reflex in sheep and on the potential use of the groove to prevent the fermentation of food in the rumen. Br J Nutr 1969;23:415420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Clements JA, Heading RC, Nimmo WS, et al. Kinetics of acetaminophen absorption and gastric emptying in man. Clin Pharmacol Ther 1978;24:420431.

  • 6.

    Lohmann KL, Roussel AJ, Cohen ND, et al. Comparison of nuclear scintigraphy and acetaminophen absorption as a means of studying gastric emptying in horses. Am J Vet Res 2000;61:310315.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Marshall TS, Constable PD, Crochik SS, et al. Determination of abomasal emptying rate in suckling calves by use of nuclear scintigraphy and acetaminophen absorption. Am J Vet Res 2005;66:364374.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Doherty TJ, Andrews FM, Provenza MK, et al. Acetaminophen as a marker of gastric emptying in ponies. Equine Vet J 1998;30:349351.

  • 9.

    Schaer S, Herrli-Gygi M, Kosmeas N, et al. Characteristics of acetaminophen absorption in healthy unweaned calves as an indirect measurement of the oroduodenal transit rate of liquid meals. J Vet Med A Physiol Pathol Clin Med 2005;52:325332.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Lateur-Rowet HJM, Breuking HJ. The failure of the oesophageal groove reflex, when fluids are given with an oesophageal feeder to newborn and young calves. Vet Q 1983;5:6874.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Herrli-Gygi M, Steiner A, Doherr MG, et al. Digestive process in ruminal drinkers characterized by means of the acetaminophen absorption test. Vet J 2008;176:369377.

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  • 12.

    Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 1980;10(suppl 2):291S298S.

  • 13.

    Sen I, Constable PD, Marshall TS. Effect of suckling isotonic or hypertonic solutions of sodium bicarbonate or glucose on abomasal emptying rate in calves. Am J Vet Res 2006;67:13771384.

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  • 14.

    Nouri M, Constable PD. Comparison of two oral electrolyte solutions and route of administration on the abomasal emptying rate of Holstein-Friesian calves. J Vet Intern Med 2006;20:620626.

    • Crossref
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  • 15.

    Clarke CR, Short CR, Hsu RC, et al. Pharmacokinetics of gentamicin in the calf: developmental changes. Am J Vet Res 1985;46:24612466.

  • 16.

    Wang LH, Rudolph AM, Benet LZ. Distribution and fate of acetaminophen conjugates in fetal lambs in utero. J Pharmacol Exp Ther 1985;235:302307.

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  • 17.

    Baumik A, Sharma MC, Lal SB. Clinicopathological studies in paracetamol-induced hepatopathy in sheep. Indian J Anim Sci 1995;65:183185.

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  • 18.

    Chaudhary RK, Srivastava AK. Pharmacokinetics of paracetamol administered with cefuroxime in crossbred calves. Indian Vet J 1999;76:973975.

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Assessment of the acetaminophen absorption test as a diagnostic tool for the evaluation of the reticular groove reflex in lambs

Kamran SharifiDepartment of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashad, Iran.

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Walter GrünbergDepartment of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, 3584 CN Utrecht, The Netherlands.

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Sarang SorooriDepartment of Clinical Sciences, School of Veterinary Medicine, University of Tehran, Tehran, Iran.

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Mehrdad MohriDepartment of Clinical Sciences, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashad, Iran.

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Mohamad Saeed Ahrari-KhafiDepartment of Clinical Sciences, School of Veterinary Medicine, University of Tehran, Tehran, Iran.

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Abstract

Objective—To assess the acetaminophen absorption test (APAT) for use in determining function of the reticular groove reflex in lambs.

Animals—12 Baluchi lambs.

Procedures—2 consecutive APATs were performed at each of 3 developmental stages (stage 1, before weaning; stage 2, at weaning; and stage 3, after weaning). Lambs suckled a test solution consisting of acetaminophen and barium sulfate and 1 week later were tube fed the same test solution. Abdominal radiographs were obtained immediately after administration of the test solution. Plasma acetaminophen concentrations were determined before and 30, 60, 90, 120, 150, and 180 minutes after intake of the test solution.

Results—Closure of the reticular groove after suckling the test solution was confirmed in all 12 lambs at stage 1, in 8 lambs at stage 2, and in 0 lambs at stage 3. Maximum plasma acetaminophen concentrations and area under the plasma acetaminophen concentration-time curves from 0 to 180 minutes were significantly higher in lambs suckling the test solution, compared with values for tube-fed lambs. Receiver operating characteristics analysis revealed that the plasma acetaminophen concentration at 60 minutes after administration was best suited to determine closure of the reticular groove in lambs.

Conclusions and Clinical Relevance—Results suggested that the APAT can be a useful diagnostic instrument to assess function of the reticular groove reflex in lambs. We propose a cutoff value for the plasma acetaminophen concentration of 25 μg/mL at 60 minutes after administration to determine function of the reticular groove mechanism in lambs.

Abstract

Objective—To assess the acetaminophen absorption test (APAT) for use in determining function of the reticular groove reflex in lambs.

Animals—12 Baluchi lambs.

Procedures—2 consecutive APATs were performed at each of 3 developmental stages (stage 1, before weaning; stage 2, at weaning; and stage 3, after weaning). Lambs suckled a test solution consisting of acetaminophen and barium sulfate and 1 week later were tube fed the same test solution. Abdominal radiographs were obtained immediately after administration of the test solution. Plasma acetaminophen concentrations were determined before and 30, 60, 90, 120, 150, and 180 minutes after intake of the test solution.

Results—Closure of the reticular groove after suckling the test solution was confirmed in all 12 lambs at stage 1, in 8 lambs at stage 2, and in 0 lambs at stage 3. Maximum plasma acetaminophen concentrations and area under the plasma acetaminophen concentration-time curves from 0 to 180 minutes were significantly higher in lambs suckling the test solution, compared with values for tube-fed lambs. Receiver operating characteristics analysis revealed that the plasma acetaminophen concentration at 60 minutes after administration was best suited to determine closure of the reticular groove in lambs.

Conclusions and Clinical Relevance—Results suggested that the APAT can be a useful diagnostic instrument to assess function of the reticular groove reflex in lambs. We propose a cutoff value for the plasma acetaminophen concentration of 25 μg/mL at 60 minutes after administration to determine function of the reticular groove mechanism in lambs.

The reticular groove reflex plays an essential role in the digestive physiologic processes of preweaned ruminants by allowing liquid ingesta to bypass the ruminant forestomachs and directly enter the abomasum from the cardia. Disturbed function of the reticular groove mechanism results in a disruption of the physiologic flow of liquid nutrients into the duodenum in preweaned ruminants. In adult ruminants, the reticular groove reflex has received attention for its potential use with orally administered drugs.1–4 Investigators exploring the effect of this mechanism on the kinetics of drugs or dietary products have frequently failed to confirm closure of the reticular groove because a practical and inexpensive diagnostic tool to determine the function of this mechanism has not been readily available. In a clinical setting, a noninvasive diagnostic test would allow clinicians to identify a possible malfunction of the reticular groove mechanism and facilitate the diagnostic evaluation of preweaned ruminants with digestive problems.

The APAT is based on the oral administration of acetaminophen, an analgesic and antipyretic agent that is only absorbed in the small intestines, and subsequent determination of plasma concentrations of this agent at various times after drug administration. This test is widely used as an indirect measurement of gastric emptying in a number of species and has been validated as a means of determining abomasal emptying time in calves.5–8 Studies9–11 in calves with chronic failure of the reticular groove mechanism have revealed that function of the reticular groove has considerable impact on the pharmacokinetics of acetaminophen in ruminants. Therefore, the APAT could be a valuable, minimally invasive, and inexpensive diagnostic tool for use in assessing function of the reticular groove reflex. Thus, the objectives of the study reported here were to evaluate differences in the pharmacokinetics of acetaminophen in young ruminants following drug ingestion with and without induction of the reticular groove reflex and to validate the APAT as a diagnostic test for use in determining function of the reticular groove reflex.

Materials and Methods

Animals—Twelve female Baluchi lambs were used for the study. Lambs were offspring of university-owned Baluchi ewes, and they were maintained in the flock to allow them to suckle from their dams. To train lambs to suckle from a nipple, animals were offered milk replacer from a nipple bottle once daily in the morning beginning approximately 1 week after birth. Lambs also had access to alfalfa hay at all times. All methods were in compliance with the guide for the care and use of agricultural animals in agricultural research and teaching.

Procedures—Two consecutive APATs were performed at a 1-week interval in the lambs at each of 3 developmental stages. Stage 1 (before weaning) was before lambs were weaned, stage 2 (at weaning) was at the time lambs were weaned, and stage 3 (after weaning) was after lambs were weaned. Mean ± SD age of lambs at stages 1, 2, and 3 was 10 ± 2 weeks, 16 ± 2 weeks, and 22 ± 2 weeks, respectively.

For the first APAT of each stage, lambs were allowed to suckle a test solution consisting of 20 mL of tap water, acetaminophena (50 mg/kg), and 30% barium sulfate solution (10 mL/kg) from a nipple bottle. The second APAT was performed 1 week later, but with the same test solution administered via an orogastric tube inserted into the rumen of each lamb.

On the morning of each APAT, lambs were weighed, and a 16-gauge catheterb was aseptically inserted in a jugular vein. Blood samples were obtained immediately before administration of the test solution (time 0) and 30, 60, 90, 120, 150, and 180 minutes after administration. Collected blood samples were immediately transferred into 10-mL tubes that contained potassium oxalate; tubes were then centrifuged (1,800 X g for 15 minutes). Plasma was harvested and stored at −20°C until analyzed for plasma acetaminophen concentration by use of a spectrophotometric technique described elsewhere.7

Immediately after administration of the test solution, abdominal radiographsc were obtained. The unsedated lambs were manually restrained in left lateral recumbency. Radiographs were examined to determine location of the barium sulfate in the forestomachs, thus allowing investigators to assess activation of the reticular groove reflex. All radiographs were interpreted by veterinary radiologists who were unaware of the treatment administered to each lamb. Only lambs that had proper closure of the reticular groove when suckling the test solution (as determined radiographically) were included for the analysis of stages 1 and 2. For stage 3, proper function of the reticular groove reflex was not used as an inclusion criterion because none of the lambs had complete closure of the reticular groove. Osmolalities of the test solutions with the lowest and highest acetaminophen concentration were determined by use of freezing-point depression.d

Data analysis—The Cmax and Tmax were obtained from a plot of the plasma acetaminophen concentration-time data. The value for AUCAcet was calculated by use of the trapezoidal rule to provide an index of the amount of acetaminophen absorbed for each treatment. An ROC analysis was performed to assess accuracy of the AUCAcet and the plasma acetaminophen concentration at specific time points to determine function of the reticular groove reflex.

Statistical analysis—Data were expressed as mean ± SD. Normal distribution of data was tested by determining the Shapiro-Wilk W and associated P value and by screening the normal probability plots. When necessary, values were logarithmically transformed to achieve a normal distribution. A repeated-measures ANOVA was used to detect differences in measured or calculated variables among stages and over time. A paired 2-tailed t test was used to determine differences between treatments. Bonferroni adjusted P values were used to assess differences within and among stages whenever the F test was significant. Values of P < 0.05 were considered significant. The ROC curves were plotted for AUCAcet and the Acet-T60. The AUC for the ROC curve was calculated for both of these curves by use of the trapezoidal rule. A statistical software programe was used for all analyses.

Results

All lambs remained healthy throughout the study. Volume of test solution administered to each lamb ranged from 87 mL for the smallest lamb (body weight, 6.7 kg) in stage 1 to 370 mL for the heaviest lamb (body weight, 35 kg) in stage 3. Osmolalities of the test solutions ranged from 199 to 218 mOsm/kg.

Suckling of the test solution resulted in complete closure of the reticular groove, as determined by use of radiography, in all 12 lambs at stage 1 (Figure 1). In contrast, examination of radiographs revealed no or incomplete closure of the reticular groove in 4 lambs at stage 2 (Figure 2). Therefore, data obtained from those 4 lambs from both APATs of stage 2 were not included in the data analysis. At stage 3, none of the lambs that suckled the test solution had radiographic evidence of radiopaque material in the forestomachs, which indicated no or incomplete closure of the reticular groove in all lambs. Because all lambs at stage 3 had failure of the reticular groove mechanism, data obtained for all lambs at stage 3 were included in the analysis.

Figure 1—
Figure 1—

Lateral radiographic view of the abdomen of a lamb at the first stage (mean ± SD age, 10 ± 2 weeks) immediately after suckling a test solution containing acetaminophen and barium sulfate. Notice that the barium sulfate in the test solution is located in the abomasum and not in the reticulum, which indicates complete closure of the reticular groove.

Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.820

Figure 2—
Figure 2—

Lateral radiographic view of the abdomen of a lamb at the second stage (mean ± SD age, 16 ± 2 weeks) immediately after suckling a test solution. Notice that the barium sulfate in the test solution is located in the forestomachs, which indicates no or incomplete closure of the reticular groove.

Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.820

Mean plasma acetaminophen concentrations at the various stages and for the 2 treatments over time were plotted (Figure 3). The Cmax values determined for lambs when they suckled the test solution and when they were tube fed the test solution at each developmental stage were summarized (Table 1). The Cmax and AUCAcet were significantly higher for lambs when they suckled the test solution than when they were tube fed the test solution at stages 1 and 2, but were in a similar range for both treatments at stage 3 (Table 2). The mean ± SD AUCAcet of lambs when suckling the test solution decreased (but not significantly) in stages 1 and 3 (61.4 ± 26.7 mg·h/mL, 63.9 ± 17.1 mg·h/mL, and 48.8 ± 24.3 mg·h/mL for stages 1, 2, and 3, respectively), whereas mean AUCAcet increased (but not significantly) when lambs were tube fed in stages 1 and 3 (36.4 ± 15.7 mg·h/mL, 35.4 ± 28.0 mg·h/mL, and 52.9 ± 24.0 mg·h/mL for stages 1, 2, and 3, respectively).

Figure 3—
Figure 3—

Plasma acetaminophen concentration over time for lambs when suckling a test solution (solid line) and when tube fed the test solution (dashed line) at stage 1 (A), stage 2 (B), and stage 3 (C) of the study. Notice that the scale on the y-axis differs among panels. The onset of administration of the test solution is indicated (arrow) and is designated as time 0. In all 3 panels, a proposed cutoff value of 25 μg/mL is indicated (horizontal dotted line). *Value for this time point differs significantly (P < 0.05) from the value for time 0. †Within a time point, values differ significantly (P < 0.05) between treatments.

Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.820

Table 1—

Mean ± SD values for Cmax and Tmax for 12 lambs administered acetaminophen (50 mg/kg) by suckling from a nipple bottle (suckled) or via an orogastric tube (tube fed) at 3 stages of development.

StagenCmax (μg/mL)Tmax (min)
SuckledTube fedSuckledTube fed
11235.6 ± 14.0*18.1 ± 13.76090
2838.5 ± 14.2*15.1 ± 13.66060
31220.9 ± 13.922.4 ± 11.99090

Stage 1 was before weaning, stage 2 was at weaning, and stage 3 was after weaning; mean ± SD age of lambs was 10 ± 2 weeks, 16 ± 2 weeks, and 22 ± 2 weeks for stages 1, 2, and 3, respectively.

Within a row, value differs significantly (P < 0.05) from the value for tube fed.

Only 8 lambs had complete closure of the reticular groove and provided data for the analysis.

None of the lambs had complete closure of the reticular groove, but the data for all 12 lambs were included in the analysis.

n = Number of lambs that provided data for the analysis.

Table 2—

Mean ± SD values for AUCAcet for 12 lambs administered acetaminophen (50 mg/kg) by suckling from a nipple bottle (suckled) or via an orogastric tube (tube fed) at 3 stages of development.

StageTreatmentAUCAcet (mg·h/mL)
1Suckled61.4 ± 26.7*
Tube fed36.4 ± 15.7
2Suckled63.9 ± 17.1*
Tube fed35.4 ± 28.0
3Suckled48.8 ± 24.3
Tube fed52.9 ± 24.0

Within a stage, value differs significantly (P < 0.05) from value for tube fed.

See Table 1 for remainder of key.

Results of ROC analysis that compared the suitability of Acet-T60 and AUCAcet to the criterion-referenced standard (ie, radiography) were determined (Figure 4). The AUC for the ROC curve for Acet-T60 was 0.70, and the AUC for the ROC curve for AUCAcet was 0.59. From these data, a cutoff value for Acet-T60 with optimal sensitivity and specificity was determined; the cutoff value was 24.9 μg/mL, which yielded a sensitivity of 0.80 and a specificity of 0.89.

Figure 4—
Figure 4—

The ROC plots for Acet-T60 (solid line) and AUCAcet (dotted line) determined for 12 lambs at stage 1, 8 lambs at stage 2, and 12 lambs at stage 3. Sensitivity (horizontal dashed lines) and specificity (vertical dashed lines) were determined for suggested cutoff values of 24.9 μg/mL (point A) and 26.3 μg/mL (point B) for Acet-T60.

Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.820

Discussion

The primary objective of the study reported here was to compare results of APATs in young ruminants when acetaminophen was administered with and without stimulation of the reticular groove reflex. Analysis of the results indicated that Cmax and AUCAcet after stimulation of the reticular groove mechanism were nearly double the values when lambs were fed with an orogastric tube feeder to circumvent closure of the reticular groove. The ROC analysis indicated that Acet-T60 is a variable with reasonable accuracy for use in determining function of the reticular groove reflex and that a single blood sample obtained to determine Acet-T60 (with a cutoff value of 25 μg/mL) can be used to characterize function of the reticular groove mechanism in lambs between 8 and 24 weeks of age.

The APAT has been validated as an alternative to other more invasive and costly methods for investigating emptying rates of the stomach in humans, horses, and other species and of the abomasum in calves.6–8 Because acetaminophen is readily absorbed in the duodenum but not in the stomach, the transit of this substance through the stomach is considered to be the rate-limiting step for its absorption and thus its appearance in plasma.5,12

In ruminants, pharmacokinetics of acetaminophen depend on abomasal motility as well as the reticular groove mechanism that considerably impacts the transit time of ingesta from the esophagus to the duodenum. Therefore, ODT was proposed as a more accurate term than abomasal emptying rate when describing results obtained by use of the APAT in ruminants.9 The importance of the effect of the reticular groove mechanism on ODT (as determined by results of the APAT) has been reported in a study9 in which tube-fed calves had significantly lower peak plasma acetaminophen concentrations, AUCs, and delayed Tmax for acetaminophen in plasma, compared with results for suckling calves. In monogastric species, there is little evidence that relevant amounts of acetaminophen are absorbed from the stomach,5 but to our knowledge, the absorption of acetaminophen from the ruminant forestomachs has not been investigated. For the study reported here, we assumed that acetaminophen would not be absorbed from the rumenoreticulum or abomasum; however, it would be possible that a larger fraction of acetaminophen would be absorbed from the forestomachs in tube-fed lambs than in lambs suckling the test solution because of the prolonged transit time of liquid ingesta through the forestomachs.

In contrast to results of a study7 in which investigators evaluated abomasal emptying rate in calves and found that Tmax for acetaminophen was the best proxy for assessing abomasal emptying, our results suggested that the Cmax for acetaminophen at a specific time is best suited for determining function of the reticular groove mechanism. This conclusion is in agreement with the observation that the delay in acetaminophen absorption in calves with disturbed reticular groove mechanism is largely attributable to prolonged retention in the ruminoreticulum rather than to decreased abomasal motility.10 Accordingly, the effect of a disturbed reticular groove reflex is more important on Cmax than on Tmax.11

Factors affecting the abomasal emptying rate, such as osmolality or pH of the solution containing the acetaminophen, are likely to affect results of the APAT.13 In the study reported here, osmolality of the test solutions was assumed to vary because differing acetaminophen concentrations were measured. The measured osmolality of each test solution was approximately 200 mOsm/kg; thus, they were considerably less than the typical osmolality of milk or commercial milk replacers.14 The range of variation for the osmolality of the test solution was 19 mOsm/kg. Therefore, we deem it unlikely that a change in the composition of the test solution may have biased results of the APAT by affecting the abomasal emptying rate.

The numeric increases of the AUCAcet detected from stage 1 to stage 3 suggested that pharmacokinetics of acetaminophen are affected by age-dependent changes in the volume of distribution and possibly also by renal and hepatic function responsible for acetaminophen clearance. In calves, the volume of distribution in extracellular fluid, abomasal emptying rate, and capacity to metabolize acetaminophen change with age; these facts suggest that Tmax should be the most stable variable over time because Cmax and AUC will be influenced by other factors, including volume of distribution and rate of elimination.15,16

Analysis of results of several experiments performed on preweaned calves administered acetaminophen (50 mg/kg) mixed in whole milk or casein-based milk replacer revealed a considerably lower Cmax than that in the study reported here and also revealed biphasic curves for plasma acetaminophen concentrations.7 Results of an in vitro study11 in which investigators evaluated characteristics of acetaminophen binding in clotted milk suggest that when acetaminophen is mixed in milk or casein-based milk replacer, a large fraction of acetaminophen transits the abomasum rapidly with the whey fraction of milk, and the remainder of the acetaminophen is bound to curd. It is assumed that these characteristics of acetaminophen in clotted milk are the underlying cause for the biphasic passage of acetaminophen through the abomasum and thus a biphasic plasma acetaminophen concentration. Because the test solution did not contain milk or milk replacer, a monophasic plasma acetaminophen concentration curve and a higher Cmax would have been anticipated. This assumption is supported by results of a study13 in which investigators compared plasma acetaminophen concentrations in calves fed casein-based milk replacer and various electrolyte solutions; a considerably lower Cmax and delayed Tmax were detected in calves receiving acetaminophen in milk replacer.

To our knowledge, the safety of acetaminophen in ruminants after oral administration has not been directly investigated. Intravenous administration of acetaminophen to calves at dosages up to 50 mg/kg does not result in clinically appreciable adverse effects of hepatotoxicosis.17,18 In sheep, acetaminophen toxicosis has been associated with injectable formulations. The main pathologic finding is hepatopathy, which has been identified in sheep administered a single dose of acetaminophen (400 mg/kg), IV. Other changes in the serum biochemical profile of sheep with acetaminophen toxicosis are hypoglycemia, which is associated with interference of normal carbohydrate metabolism; a decrease in the albumin-to-globulin ratio; and hypercholesterolemia.17 Therefore, we believe that an APAT conducted by use of a dosage of 50 mg/kg in young ruminants does not pose any risk of toxic effects.

Analysis of our results indicated that the APAT can be a valuable diagnostic tool for use in determining function of the reticular groove mechanism. Evaluation of the Acet-T60 revealed the strongest differences between lambs with and without closure of the reticular groove. Analysis of our results suggested that this variable is reasonably accurate for use in determining function of the reticular groove with an AUC for the ROC curve of 0.70. We propose that a cutoff value for Acet-T60 of 25 μg/mL (which yielded a sensitivity of 0.80 and a specificity of 0.89) be used for evaluation of lambs between 8 and 22 weeks of age.

ABBREVIATIONS

Acet-T60

Plasma acetaminophen concentration 60 minutes after treatment

APAT

Acetaminophen absorption test

AUC

Area under the plasma concentration-time curve

AUCAcet

Area under the plasma acetaminophen concentration-time curve from 0 to 180 minutes after administration

Cmax

Maximum concentration

ODT

Oroduodenal transit time

ROC

Receiver operating characteristics

Tmax

Time of maximum concentration

a.

Generously supplied by Borhan Daru Co, Mashhad, Iran.

b.

Polyflon, Poly Medicure Ltd, Faridabad, India.

c.

Shimadzu MD 100p, Shimadzu Corp, Kyoto, Japan.

d.

Advanced osmometer 3MO, Advanced Instruments, Norwood, Mass.

e.

SAS, version 9.1.3, SAS Institute Inc, Cary, NC.

References

  • 1.

    Constable PD, Wittek T, Ahmed AF, et al. Abomasal pH and emptying rate in the calf and dairy cow and the effect of commonly administered therapeutic agents, in Proceedings. 24th World Buiatrics Cong 2006;5468.

    • Search Google Scholar
    • Export Citation
  • 2.

    Goff JP, Horst RL. Oral administration of calcium salts for treatment of hypocalcemia in cattle. J Dairy Sci 1993;76:101108.

  • 3.

    Scholz H. Utilization of the reticular groove contraction in adult cattle—a therapeutic alternative for the practitioner? Bovine Pract 1988;23:148152.

    • Search Google Scholar
    • Export Citation
  • 4.

    Orskov ER, Benzie D. Studies on the oesophageal groove reflex in sheep and on the potential use of the groove to prevent the fermentation of food in the rumen. Br J Nutr 1969;23:415420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Clements JA, Heading RC, Nimmo WS, et al. Kinetics of acetaminophen absorption and gastric emptying in man. Clin Pharmacol Ther 1978;24:420431.

  • 6.

    Lohmann KL, Roussel AJ, Cohen ND, et al. Comparison of nuclear scintigraphy and acetaminophen absorption as a means of studying gastric emptying in horses. Am J Vet Res 2000;61:310315.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Marshall TS, Constable PD, Crochik SS, et al. Determination of abomasal emptying rate in suckling calves by use of nuclear scintigraphy and acetaminophen absorption. Am J Vet Res 2005;66:364374.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Doherty TJ, Andrews FM, Provenza MK, et al. Acetaminophen as a marker of gastric emptying in ponies. Equine Vet J 1998;30:349351.

  • 9.

    Schaer S, Herrli-Gygi M, Kosmeas N, et al. Characteristics of acetaminophen absorption in healthy unweaned calves as an indirect measurement of the oroduodenal transit rate of liquid meals. J Vet Med A Physiol Pathol Clin Med 2005;52:325332.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Lateur-Rowet HJM, Breuking HJ. The failure of the oesophageal groove reflex, when fluids are given with an oesophageal feeder to newborn and young calves. Vet Q 1983;5:6874.

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Contributor Notes

Supported by the Administration of the Dean for Research of Ferdowsi University of Mashhad, Mashhad, Iran (approval No. 49253-9/12/84).

Presented in part at the 13th International Conference on Production

Diseases in Farm Animals, Leipzig, Germany, July–August 2007.

The authors thank Mahdi Khorsandi and Dr. Arash Omidi for technical assistance.

Address correspondence to Dr. Sharifi.